U.S. Patent: 5143922 - Tricyclic thromboxane A.sub.2 antagonists

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United States Patent	*5,143,922*
Oshima , et al.	September 1, 1992

Tricyclic thromboxane A.sub.2 antagonists

Abstract

Novel tricyclic compounds having a TXA.sub.2 antagonizing activity represented by formula (I): ##STR1## possess a potent antagonizing action against thromboxane A.sub.2 and also an antiallergic and/or antihistaminic acitvity, and are expected to have preventive and therapeutic effects on ischemic diseases, cerebro-vascular diseases, etc.

Inventors:	Oshima; Etsuo (Shizuoka, JP); Obase; Hiroyuki (Mishima, JP); Karasawa; Akira (Shizuoka, JP); Kubo; Kazuhiro (Shizuoka, JP); Miki; Ichiro (Tokyo, JP); Ishii; Akio (Shizuoka, JP); Ishii; Hidee (Shizuoka, JP); Ohmori; Kenji (Mishima, JP)
Assignee:	Kyowa Hakko Kogyo Co., Ltd. (Tokyo, JP)
Appl. No.:	616095
Filed:	November 20, 1990

Foreign Application Priority Data

	Dec 14, 1987[JP]	62-315769
	Feb 03, 1988[JP]	63-23543

Current U.S. Class: 514/320; 514/212.01; 514/217.11; 514/382; 514/422; 540/596; 544/359; 544/366; 544/370; 544/375; 544/380; 546/16; 546/196; 546/202; 546/203; 546/204; 548/251; 548/525; 548/527

Intern'l Class: A61K 031/445; C07D 405/12

Field of Search: 546/196 540/596 548/251,525 514/213,320,422,382

References Cited U.S. Patent Documents

3354155	Nov., 1967	Tretter	260/240.
3420851	Jan., 1969	Bloom et al.	260/333.
4282365	Aug., 1981	Rokach et al.	548/252.
4585788	Apr., 1986	Helsley et al.	514/450.
4596809	Jun., 1988	Takizawa et al.	514/25.
4749703	Jun., 1988	Uso et al.	514/253.
4912222	Mar., 1990	Griffith et al.	546/196.
Foreign Patent Documents
0085870	Aug., 1983	EP.
188802	Jul., 1986	EP.
214779	Mar., 1987	EP.
0235796	Sep., 1987	EP.
2407661	Aug., 1974	DE.
152673	Jul., 1986	JP.
152674	Jul., 1986	JP.
152675	Jul., 1986	JP.
152676	Jul., 1986	JP.
257981	Nov., 1986	JP.
153280	Jul., 1987	JP.
1330966	Sep., 1973	GB.
1347935	Feb., 1974	GB.

Other References

J. Med. Chem. 19, 941 (1976).
J. Med. Chem. 20, 1499 (1977).
J. Med. Chem. 21, 633 (1978).
Drugs, 13, 161 (1977).
Arz.-Forsch., 13, 1039 (1963).
Arz.-Forsch., 14, 100 (1964).
J. Med. Chem. 21, 633 (1978).
Chem. Abstracts, vol. 72, 308 (1970) No. 3387d.
Chem. Abstracts, vol. 81, 424 (1974), No. 25566z.
Eur. J. Med. Chem.--Chimica Therapeutica, P. Dostert et al., "Composes Tricycliques portant une chaine alkylaminoalkylthio. Synthese et activite pharmacologique," May-Jun. 1974-1979, No. 3, p. 259.
J. Med. Chem., M. Cerelli et al., "Antiinflammatory and Aldose Reductase Inhibitory Activity of Some Tricyclic Arylacetic Acids," vol. 29, 2347 (1986).

Primary Examiner: Ivy; C. Warren
Assistant Examiner: Turnipseed; James H.
Attorney, Agent or Firm: Fitzpatrick, Cella, Harper & Scinto

Parent Case Text

This application is a division of application Ser. No. 07/281,545 filed Dec. 8, 1988, now U.S. Pat. No. 4,994,463, issued Feb. 19, 1991.

Claims

What is claimed is:

1. A tricyclic compound represented by formula (I): ##STR137## wherein represents single bond or double bond; W represents --S--or .dbd.CH--;

n is 1, 2, 3, or 4;

one of R.sup.A and R.sup.B represents hydrogen and the other represents --Y--M wherein Y represents single bond, --CR.sup.1 R.sup.2 --(CH.sub.2).sub.m --, or --CR.sup.1 .dbd.CR.sup.2 --(CH.sub.2).sub.m -- wherein each of R.sup.1 and R.sup.2 independently represents hydrogen or lower alkyl and m is 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus; and M represents --COOR.sup.3 wherein R.sup.3 represents hydrogen or lower alkyl, --CONR.sup.3a R.sup.3b wherein each of R.sup.3a and R.sup.3b independently has the same significances for R.sup.3 as described above, or tetrazolyl;

each of G.sup.A and G.sup.B independently represents lower alkyl, halogen, hydroxyl, or lower alkoxyl;

each of g.sup.A and g.sup.B independently represents 0, 1, 2 or 3;

Z represents ##STR138## wherein L represents hydrogen, hydroxyl, or lower alkoxy; E.sup.2 represents single bond, --CO--, or ##STR139## wherein R.sup.4 represents hydrogen or lower alkyl; and Q represents aryl having 6 to 10 carbon atoms, aralkyl having 7 to 20 carbon atoms or aralkenyl having 8 to 18 carbon atoms which is optionally substituted with 1 to 3 substituents on the aromatic ring, selected from the group consisting of lower alkyl, halogen, trifluoromethyl, hydroxyl, lower alkoxyl and methylenedioxy formed together with the ortho-position of the aromatic ring; ##STR140## wherein Q has the same significance as described above; p is 1, 2 or 3;

and a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein one of R.sup.A and R.sup.B represents hydrogen and the other represents --Y--COOH.

3. A compound according to claim 2, wherein Y is a member selected from the group consisting of single bond, ##STR141##

4. A compound according to claim 3, wherein n is 2 and W represents --S--.

5. A compound according to claim 3, wherein n is 1 or 2 and W represents .dbd.CH--.

6. A compound according to any one of claims 4 and 5, wherein Z is ##STR142## and p is 2 or 3.

7. A compound according to any one of claims 4 and 5, wherein p is 2; and Z is ##STR143## wherein L represents hydrogen or hydroxyl, E.sup.2 represents single bond or --CO', and Q is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzhydryl, phenethyl, stryl, cinnamyl.

8. A compound according to claim 2, which is selected from the group consisting of

11-[2-(4-phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ca rboxylic acid,

11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ca rboxylic acid,

11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ac etic acid,

2-methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e ]oxepin-2-yl]propionic acid,

11-[2-[4-(4-chlorobenzyl)-1-piperidinyl]ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid,

2-methyl-2-[11-[2-[4-(4-chlorobenzyl)-1-piperidinyl]ethyl]thio-6,11-dihydro dibenz[b,e]oxepin-2-yl]propionic acid,

11-[3-(4-benzyl-1-piperidinyl)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2- carboxylic acid,

11-[2-(4-benzyl-1-piperidinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-a cetic acid.

9. A compound according to claim 1, wherein said salt is selected from the group consisting of acid addition salt, metal salt, ammonium salt, organic amine addition salt and amino acid addition salt.

10. A pharmaceutical composition comprising a pharmaceutical carrier and, as an active ingredient, an effective amount of a tricyclic compound as defined by claim 1.

Description

BACKGROUND OF THE INVENTION

The present invention relates to novel tricyclic compounds which strongly antagonize an action of thromboxane A.sub.2 (hereafter referred to as TXA.sub.2) and possess an antiallergic and/or antihistaminic activity.

It is hitherto known that TXA.sub.2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1985)]. Further TXA.sub.2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA.sub.2 is considered to take part in pathological conditions over a wide range. As examples, the following diseases can be exemplified.

(1) Ischemic disease

For example, myocardial infarction, angina pectoris, and thrombosis

(2) Cerebro-vascular disease

For example, transient ischemic attack, migraine, cerebral hemorrhage, and cerebral infarction

(3) Peripheral vascular diseases and disease caused by unbalanced lipid metabolism

For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, and pulmonary embolism

(4) Inflammatory and allergic disease

For example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis

(5) Shock

(6) Cancer metastasis

Accordingly, compounds that antagonize the action of TXA.sub.2 are expected to have therapeutic effects in preventing or treating optional one or more of the diseases described above or other diseases involving TXA.sub.2. limited due to side effects mediated by TXA.sub.2 or considered to be mediated by TXA.sub.2, it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA.sub.2.

In recent years, TXA.sub.2 is also thought to play a role in the pathogenesis of allergic diseases, especially of an asthma [cf. J. Allergy Clin. Immunol., 77, 122 (1986); Arch. Pharmacol., 327, 148 (1984)].

As an antagonist of TXA.sub.2, representative compounds are exemplified in Thrombosis Research, 44, 377 (1986).

Furthermore, an indole compound having the following structure: ##STR2## and the like are disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR3## and the like are disclosed in Japanese Published Unexamined Patent Application No. 212552/1986 [West German Patent Application (DE) No. 3,508,692]. These compounds have a phenylsulfonamide group as a side chain and exhibit an activity of antagonizing TXA.sub.2.

On the other hand, in tricyclic compounds represented by the following formula: ##STR4## wherein R.sup.o as a substituent on the aromatic ring has carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as carboxylic acid group) directly or via an alkylene chain, etc. and W.sup.o is hydrogen or a substituent such as oxo (.dbd.O), methylene (.dbd.CH.sub.2), hydroxyl, alkoxyl, etc., oxepine derivatives wherein X.sub.1 --X.sub.2 is --CH.sub.2 O-- are known as showing antiinflammatory or antiallergic activities, etc [J. Med. Chem., 19, 941 (1976); ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Pat. No. 4,282,365 (Japanese Published Unexamined Patent Application No. 21679/1983); U.S. Pat. No. 4,585,788; Japanese Published Unexamined Patent Application Nos. 152673/1986; 152674/1986 and 152675/1986].

Further, it is also known that oxepine derivatives wherein R.sup.o is hydrogen or a substituent other than the carboxylic acid group, such as, alkyl, alkoxyl, halogen, etc. and W.sup.o has a (di)alkylaminoalkyl chain via --S-- show antiasthmatic activities [Japanese Published Unexamined Patent Application No. 126883/1983 (EP 0085870A)]. It is also known that derivatives such as oxepine or thiepine (wherein X.sub.1 --X.sub.2 is --CH.sub.2 S--) wherein W.sup.o is alkylaminoalkylidene show an antidepressant action, etc. [U.S. Pat. Nos. 3,354,155 and 3,420,851; Drugs, 13, 161 (1977); Arz.Forsch., 13, 1039 (1963); ibid., 14, 100 (1964)]. Furthermore, it is also known that derivatives such as cycloheptene (wherein X.sub.1 --X.sub.2 is --CH.dbd.CH--) or thiepine wherein -W.sup.o has an alkyl chain substituted with an alicyclic nitrogen-containing heterocyclic group such as piperazine, etc. at the terminal thereof via --NHCO-- are known to have a calcium antagonizing activity [Japanese Published Unexamined Patent Application Nos. 47466/1986 (EP 191867A) and 153280/1987].

Further oxepine derivatives having an antiallergic activity wherein R.sup.o has a carboxylic acid group and W.sup.o has a (di)alkylaminoalkyl chain via --S-- are known [Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S. Pat. No. 4,596,804); 152669/1986, 152670/1986, 152671/1986 and 15672/1986 (all of them correspond to EP 188802A); 152676/1986 and 257981/1986]. Furthermore, oxepine or cycloheptene (wherein X.sub.1 --X.sub.2 is --CH.sub.2 CH.sub.2 --) derivatives showing an antihistaminic activity wherein W.sup.o is a (di)alkylaminoalkylidene are known [Japanese Published Unexamined Patent Application No. 45557/1986 (EP 214779A)]. Still further, oxepine derivatives wherein W.sup.o is an alkylidene substituted with an alicyclic nitrogen-containing heterocyclic group such as 4-methylpiperazinyl, 4-methylhomopiperazinyl, piperidino, pyrrolidinyl, thiomorpholino or morpholino or with a (di)alkyl-substituted amino at the terminal thereof are known as showing an antiallergic and antiinflammatory activity [Japanese Published Unexamined Patent Application No. 10784/1988 (EP 0235796A)].

Novel and useful TXA.sub.2 antagonists are expected to have preventive and therapeutic effects on various diseases, and are in demand. Further antiallergic agents having a TXA.sub.2 -antagonizing activity are expected to have preventive and therapeutic effects on allergic diseases, and are in demand.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel tricyclic compounds having a TXA.sub.2 -antagonizing activity and antiallergic activity by containing both a carboxylic acid group as the foresaid R.sup.o, and, as the aforesaid W.sup.o, an alkylthio chain or alkylidene chain substituted at the terminal thereof with an alicyclic nitrogen-containing heterocyclic group having a substituent such as aryl, aralkyl, etc. thereon.

The present invention relates to a tricyclic compound [hereafter referred to as Compound (I); compounds having other formula numbers are also the same] represented by formula (I): ##STR5## wherein represents single bond or double bond; X.sub.1 --X.sub.2 represents --CH.sub.2 O--, ##STR6## wherein l represents 0, 1 or 2, --CH.sub.2 --CH.sub.2 --, or --CH.dbd.CH--;

W represents -S-or .dbd.CH--;

n is 1, 2, 3, or 4;

one of R.sup.A and R.sup.B represents hydrogen and the other represents --Y--M wherein Y represents single bond, --CR.sup.1 R.sup.2 --(CH.sub.2).sub.m --, or --CR.sup.1 .dbd.CR.sup.2 --(CH.sub.2).sub.m -- wherein each of R.sup.1 and R.sup.2 independently represents hydrogen or lower alkyl and m is 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus; and M represents --COOR.sup.3 wherein R.sup.3 represents hydrogen or lower alkyl, --CONR.sup.3a R.sup.3b wherein each of R.sup.3a and R.sup.3b independently has the same significances for R.sup.3 as described above, or tetrazolyl;

each of G.sup.A and G.sup.B independently represents lower alkyl, halogen, hydroxyl, or lower alkoxyl;

each of g.sup.A and g.sup.B independently represents 0, 1, 2 or 3;

Z represents ##STR7## wherein E.sup.1 represents single bond, --CO--, --COO-- wherein the left side of the formula is bound to the nitrogen atom, or --SO.sub.2 --; and Q represents optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, aromatic heterocyclic group, or ##STR8## wherein L represents hydrogen, hydroxyl, or lower alkoxy; E.sup.2 represents single bond, --CO--, or ##STR9## wherein R.sup.4 represents hydrogen or lower alkyl; and Q has the same significance as described above; ##STR10## wherein Q has the same significance as described above; or ##STR11## p is 1, 2 or 3; and a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the definition of Z in formula (I), the aryl is exemplified by phenyl and naphthyl having 6 to 10 carbon atoms, etc.; the aralkyl is exemplified by benzyl, phenethyl, benzhydryl and trityl, etc. having 7 to 20 carbon atoms, etc.; and the aralkenyl is exemplified by styryl and cinnamyl having 8 to 18 carbon atoms, etc. The substituent on each group means independently 1 to 3 substituents on the aromatic ring and includes a group selected from lower alkyl, halogen, trifluoromethyl, hydroxyl, lower alkoxyl and methylenedioxy formed together with the ortho-position thereof. Likewise, the aromatic heterocyclic group shown by Q represents a group selected from furyl, thienyl, pyridyl, pyrimidinyl, quinolyl and isoquinolyl.

Further in the definition of each group in formula (I), the alkyl moiety in the lower alkyl and lower alkoxyl is a straight or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, neopentyl, hexyl, etc.; the halogen includes, for example, fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salt of Compound (I) includes an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, etc. which are pharmaceutically acceptable.

As the pharmaceutically acceptable acid addition salt of Compound (I), mention may be made of the inorganic acid salt such as hydrochloride, sulfate, phosphate, etc. and the organic acid salt such as acetate, malate, fumarate, tartarate, citrate, etc. As the pharmaceutically acceptable metal salt, the alkali metal salt such as sodium salt, potassium salt, etc.; alkaline earth metal salt such as magnesium salt, calcium salt, etc. and further the aluminum salt and the zinc salt are appropriate. As the ammonium salt, mention may be made of the salt of ammonium, tetramethylammonium, etc. As the pharmaceutically acceptable organic amine addition salt, mention may be made of an addition salt of morpholine, piperidine, etc. As the pharmaceutically acceptable amino acid addition salt, an addition salt of lysine, glycine, phenylalanine and the like are mentioned.

Hereafter processes for producing Compound (I) are described but the production of Compound (I) is not deemed to be limited thereto. Further in various processes, the reaction conditions can be appropriately chosen from those described below.

The reaction solvent may be chosen from water or an organic solvent which does not participate in the reaction and can be used alone or in combination. The organic solvent includes, for example, an alcohol such as methanol, ethanol, propanol, isopropanol, etc.; an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, etc.; a hydrocarbon such as benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, ligroin, decalin, etc.; a ketone such as acetone, methyl ethyl ketone, etc.; and amide such as formamide, dimethylformamide, hexamethylphosphoric triamide, etc.; acetonitrile, ethyl acetate, dimethylsulfoxide, sulfolane or a halogenated hydrocarbon such as methylene chloride, dichloroethane, tetrachloroethane, chloroform or carbon tetrachloride, etc. Further in case that bases or acids later described are liquid, they may also be used as a solvent.

As the appropriate base, an inorganic or organic base can be used. These bases include an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example, sodium carbonate, sodium hydrogencarbonate or potassium carbonate; an alkali metal acetate, for example, sodium acetate or potassium acetate; an alkali metal alkoxide, for example, sodium methoxide, sodium ethoxide or potassium tert-butoxide; or an organic metal compound, for example, sodium hydride, n-butyl lithium, sec-butyl lithium; and an organic amine, for example, triethylamine, tri-n-butylamine, pyridine, N,N-dimethylaminopyridine, picoline, lutidine, N,N-dimethylaniline, dicyclohexylmethylamine, N-methylpiperidine, morpholine, diazabicyclooctane, diazabicycloundecene or N-benzyltrimethylammonium hydroxide (Triton B), etc.

As the appropriate acid, an inorganic or organic acid or Lewis acid can be used. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, hypochloric acid, sulfurous acid or nitrous acid, etc. Examples of the organic acid include formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid or methanesulfonic acid, etc. Examples of the Lewis acid include aluminum chloride, zinc chloride, tin chloride, boron trifluoride, boron trifluoride diethyl ether complex, titanium tetrachloride, etc.

The reaction temperature is generally from -80.degree. C. to a boiling point of a solvent. Heating without a solvent is also possible. The reaction may generally be carried out under normal pressure but it is also possible to apply pressure. In this case, the reaction temperature may be raised to a temperature higher than the boiling point of a solvent.

The reaction time is generally in a range of one minute to one week.

In the following description, preferred reaction conditions are given.

Further in the following description, the tricyclic moiety which does not directly participate in the reaction: ##STR12## wherein , X.sub.1 --X.sub.2, R.sup.A, R.sup.B, G.sup.A, G.sup.B, g.sup.A and g.sup.B have the same significances as described above; is sometimes referred to as ##STR13##

Compound (I) can be prepared from Compound (II) or from Compounds (IIIa through d), etc. obtained from Compound (II) according to the following reaction steps: ##STR14## wherein ##STR15## has the same significance as described above; R.sup.5 represents lower alkyl, Hal represents halogen and Ph represents phenyl.

Herein the halogen shown by Hal represents chlorine, bromine and iodine and the lower alkyl has the same significance as defined for the lower alkyl in each group in formula (I).

Compounds (II) are either described in J. Med. Chem., 19, 941 (1976); ibid., 21, 1035 (1978); ibid., 20, 1557 (1977); ibid., 20, 1499 (1977); ibid., 29, 2347 (1986); ibid., 21, 633 (1978); ibid., 20, 456 (1977); U.S. Pat. Nos. 4,172,949 and 4,282,365; Japanese Published Unexamined Patent Application Nos. 21679/1983; 28972/1985; 152669/1986; 152672/1986; 152673/1986; 152675/1986 and 10784/1988 etc. or can be synthesized according to methods described in these publications or in a manner similar thereto.

Moreover, Compounds (IIIa to d) can be synthesized from Compound (II) according to methods described in Japanese Published Unexamined Patent Application Nos. 150083/1981; 28972/1985; 152670/1986; 152671/1986; 52672/1986; 152675/1986 and 10784/1988, etc. or in a manner similar thereto.

METHOD 1-1

Synthesis of Compound (Ia) in Compound (I), wherein W is --S-- (part 1) ##STR16## wherein X.sub.1 --X.sub.2, R.sup.A, G.sup.A, G.sup.B, Z, g.sup.A, gB, n and p have the same significances as described above.

Compound (Ia) can be obtained from Compounds (IIIa to c) and (IVa) according to the following reaction step: ##STR17## wherein A.sup.1 represents OH, OR.sup.5 or Hal; and ##STR18## Z, R.sup.5, Hal and p have the same significances as described above.

Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of an appropriate dehydration condensing agent, for example, trifluoroacetic anhydride at from 0.degree. C. to room temperature for 1 to 24 hours in an inert solvent such as methylene chloride, chloroform, etc., then adding 1 to 5 molar equivalents of Compound (IVa) or acid addition salts thereof (for example, hydrochloride, hydrobromide, acetate, trifluoroacetate, p-toluenesulfonate, etc.; the same is applied hereafter) to the reaction solution and carrying out the reaction at 0.degree. C. to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex.

Likewise, Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIb) with 1 to 5 molar equivalents of Compound (IVa) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, etc., at 0.degree. C. to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex.

Furthermore, Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIc) with 1 to 10 molar equivalents of Compound (IVa) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, dimethylformamide, etc., at 0.degree. C. to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of a base such as triethylamine, sodium hydride, etc.

METHOD 1-2

Synthesis of Compound (Ia) (part 2)

Likewise, Compound (Ia) can be obtained from Compounds (IIIa-c) according to the following reaction steps.

Firstly, Compound (VIb) or (VIc) is prepared from Compounds (IIIa-c) according to the following reaction steps: ##STR19## wherein ##STR20## A.sup.1, Hal and n have the same significances as described above; and R.sup.6 represents a group capable of being split as OR.sup.6.

Herein, R.sup.6 means, for example, alkylsulfonyl such as methanesulfonyl, trifluoromethanesulfonyl, etc. and arylsulfonyl such as phenylsulfonyl, p-toluenesulfonyl, etc.

The corresponding Compound (VIa) or (VIc) can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of an appropriate dehydrating and condensing agent, for example, trifluoroacetic anhydride, in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours, then adding 1 to 10 molar equivalents of an alcohol (Va) or its halide (Vb) to this reaction solution and carrying out the reaction at a temperature of between room temperature and the boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, for 1 to 24 hours.

Compound (VIa) or (VIc) can also be obtained by reacting Compound (IIIb) or (IIIc) with 1 to 10 molar equivalents of an alcohol (Va) or its halide (Vb) in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of between room temperature and the boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, or an appropriate base such as triethylamine for 1 to 24 hours.

Further the thus obtained Compound (VIa) may be reacted with 1 to 5 molar equivalents of Hal-R.sup.6 or (R.sup.6).sub.2 O (wherein R.sup.6 and Hal have the same significances as described above) in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from -50.degree. C. to room temperature for 1 to 24 hours to give Compound (VIb).

Furthermore, compound (VIa) may be reacted (1) with 1 to 5 molar equivalents of a halogenating agent, for example, thionyl chloride, in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours; (2) with 1 to 10 molar equivalents of an alkyl halide such as methyl iodide in an inert solvent such as benzene in the presence of 1 to 10 molar equivalents of triphenylphosphine and 1 to 10 molar equivalents of diethyl azodicarboxylate at a temperature of from -20.degree. C. to a boiling point of the solvent for 1 to 24 hours; or (3) with 1 to 10 molar equivalents of a halogenating agent, for example, methanesulfonyl chloride, in dimethylformamide in the presence of 1 to 10 molar equivalents of a base such as lithium chloride, etc., at a temperature of from -20.degree. to 100.degree. C. for 1 to 24 hours, whereby Compound (VIc) is obtained.

Where Compound (VIc) is the chloride (Hal is Cl) or bromide (Hal is Br), the compound may be reacted further with an iodide, for example, sodium iodide, in a polar solvent such as acetonitrile to give the iodide (Hal is I). Compound (VIb) can be converted into Compound (VIc) under similar conditions.

Compound (VIb) or (VIc) can be converted into Compound (Ia) according to the following reaction step: ##STR21## wherein A.sup.2 represents OR.sup.6 or Hal; and R.sup.6, Hal, ##STR22## Z, p and n have the same significances as described above

Compound (Ia) can be obtained by reacting Compound (VIb) or Compound (VIc) with 1 to 10 molar equivalents of Compound (VII), if necessary, in the presence of a molar equivalent to a largely excessive amount of a base such as sodium carbonate, triethylamine, pyridine, Triton B, sodium hydride, etc., at a temperature of between room temperature and the boiling point of the solvent for 1 to 48 hours in an inert solvent such as methylene chloride, chloroform, dichloroethane, dimethylformamide, dioxane, etc.

Further the reaction of Compound (VIc) with Compound (VII) may also be carried out in the presence of an iodide, for example, sodium iodide or potassium iodide.

METHOD 2-1

Synthesis of Compound (Ib) in Compound (I), wherein W is .dbd.CH-- (Part 1) ##STR23## wherein X.sub.1 --X.sub.2, R.sup.1, R.sup.B, G.sup.A, G.sup.B, z, n, g.sup.A, g.sup.B and p have the same significances as described above.

Compound (Ib) can be prepared according to the following reaction steps: ##STR24## wherein ##STR25## Z, Ph, n and p have the same significances as described above.

Firstly, a phosphonium salt (VIIIb): ##STR26## wherein Z, Hal, Ph, n and p have the same significances as described above, obtained by reaction triphenylphosphine (Ph.sub.3 P) with a halide: ##STR27## is treated with a molar equivalent of a base such as n-butyl lithium, etc. in an inert solvent, for example, tetrahydrofuran, etc., at 0.degree. C. to room temperature to give an ylide (VIIIa).

Compound (Ib) can be obtained by reacting 1 to 5 molar equivalents, based on Compound (II), of Compound (VIIIa), after or without isolation, with Compound (II) in an inert solvent, for example, tetrahydrofuran, etc., at a temperature of from 0.degree. C. and a boiling point of the solvent.

METHOD 2-2

Synthesis of Compound (Ib) (part 2)

Compound (Ib) can also be obtained from Compound (II) according to the following reaction steps: ##STR28## wherein ##STR29## Z, Hal, n and p have the same significances as describe a

Firstly, Compound (II) is reacted with 1 to 5 molar equivalents of Grignard reagent (IVc) in an inert solvent such as tetrahydrofuran, diethyl ether, etc., at a temperature of from 0.degree. C. to room temperature, for 1 to 48 hours to give an alcohol (IX).

Compound (IVc) can be obtained by reacting corresponding Compound (IVb) with 0.5 to 2 molar equivalents of magnesium in an inert solvent such as tetrahydrofuran, diethyl ether, etc., if necessary and desired, in the presence of a trace amount of iodine, at a temperature of from 0.degree. C. to a boiling point of the solvent for 0.5 to 12 hours. The Grignard reagent thus formed is generally used in the following reaction without isolating the same.

The thus obtained Compound (IX) can be subjected to dehydration to give Compound (Ib). For the dehydration, a method which comprises performing the reaction in an inert solvent such as dioxane, etc., in the presence of an acid, for example, p-toluenesulfonic acid, etc., at a temperature of from room temperature to boiling point of the solvent for 1 to 12 hours, or a method which comprises reacting with a halogenating agent such as thionyl chloride, etc., in an organic base such as pyridine, etc. at a temperature of from 0.degree. C. to a boiling point of the solvent for 1 to 12 hours, or the like is adopted.

METHOD 2-3

Synthesis of Compound (Ib) (part 3)

Firstly, the carbonyl group of Compound (II) is converted into Compound (Xb) according to the following reaction steps: ##STR30## wherein Ph and n have the same significances as described above, and R.sup.7 represents a hydroxyl-protecting group.

Herein, as the hydroxyl-protecting group, groups generally used as protective groups for an alcoholic hydroxyl may be used. A preferred protecting group is, for example, tetrahydropyranyl or the like.

Firstly, an ylide (VIIIc) in which hydroxyl is protected by an appropriate protective group (for example, tetrahydropyranyl, etc.) is formed in an inert solvent, for example, tetrahydrofuran [J. Org. Chem., 44, 3760 (1979)].

Then, the formed ylide (VIIIc) is reacted with 0.2 to 1 molar equivalent of Compound (II) at a temperature of from -78.degree. C. to the boiling point of the solvent for 1 to 48 hours to give Compound (Xa).

Compound (Xa) can be converted into Compound (Xb) by removing the protective group. The removal of protective group can be conducted in a conventional manner; in the case of using, for example, tetrahydropyranyl as a protective group, Compound (Xa) is treated with an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc. in a suitable hydrated solvent such as hydrated dioxane, hydrated tetrahydrofuran, etc., at a temperature of from 0.degree. C. to the boiling point of the solvent for 1 to 24 hours to give Compound (Xb).

Compound (Xb) can be led to Compound (Ib) via Compound (Xc) or Compound (Xd) by the following reaction steps: ##STR31## wherein ##STR32## Z, R.sup.6, Hal, n and p have the same significances as described above.

The reactions can be performed in a manner similar to the method for leading from Compound (VIa) to Compound (Ia) described in Method 1-2.

METHOD 2-4

Synthesis of Compound (Ib-1) in Compound (Ib) wherein n is 1 ##STR33## wherein X.sub.1 --X.sub.2, R.sup.1, R.sup.B, G.sup.A, G.sup.B, z, g.sup.A, g.sup.B and p have the same significances as described above.

Compound (Ib-1) can be prepared according to the following reaction steps: ##STR34## wherein Z, R.sup.6, Hal and p have the same significances as described above; [CH.sub.2 O] represents formaldehyde and/or a polymer thereof; R.sup.8a and R.sup.8b, which may be the same or different, each represents lower alkyl or may be combined to nitrogen adjacent thereto to form a heterocyclic ring and R.sup.9 represents lower alkyl.

Herein, the lower alkyl in the definitions of R.sup.8a, R.sup.8b and R.sup.9 has the same significance as described for the lower alkyl in formula (I). As the heterocyclic ring formed by R.sup.8a and R.sup.8b, mention may be made of pyrrolidine, piperidine, N-methylpiperazine, morpholine, thiomorpholine, N-methylhomopiperazine and the like.

Compound (IIId) is reacted with 1 to 10 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, either in a hydrohalogenic acid, preferably hydrochloric acid or in an inert solvent, for example, dioxane, saturated with hydrogen chloride and, if necessary and desired, in the presence of a strong acid such as sulfuric acid or trifluoroacetic acid, at a temperature of from room temperature to the boiling point of the solvent, for 1 to 24 hours to give Compound (Xd-1).

Further Compound (Xb-1) can be obtained under almost the same conditions as described above except that no hydrohalogenic acid is added.

Furthermore, Compound (Xd-1) can also be obtained as follows. That is, Compound (IIId) is reacted with 1 to 2 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, and 1 to 3 molar equivalents of a secondary amine (XI) and trifluoroacetic acid, in an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc., if necessary and desired, in the presence of acetic acid, at a temperature of from room temperature to the boiling point of the solvent, for 1 to 48 hours to give Compound (Xe) or acid addition salts thereof. Compound (Xe) can be led to Compound (Xd-1) by reacting with 1 to 10 molar equivalents of a halocarbonate, preferably ethyl chloroformate in an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc., if necessary, in the presence of a base such as triethyl amine and sodium acetate between at 0.degree. C. and the boiling point of the solvent for 1 to 48 hours.

The thus obtained Compounds (Xb-1) and (Xd-1) can be converted into Compound (Ib-1) as in the synthesis of Compound (Ib) from the corresponding Compounds (Xb) and (Xd) described in Method 2-3.

Further Compound (Ib-1) can also be obtained according to the method for obtaining Compound (Xe) from Compound (IIId) in which Compound (VII) is used in place of Compound (XI).

METHOD 3

Synthesis of Compound (Ic) in Compound (I), wherein Z is ##STR35## wherein , X.sub.1 --X.sub.2, R.sup.A, R.sup.B, G.sup.A, G.sup.B, W, E.sup.1, Q, g.sup.A, g.sup.B, n and p have the same significances as described above.

Compound (Ic) can be prepared from Compounds (XII) and (XIII) obtained in a manner similar to Methods 1 and 2 described above by the following reaction steps: ##STR36## wherein ##STR37## W, E.sup.1, Q, n and p have the same significances as described above and A.sup.3 represents a leaving group in --E.sup.1 --Q.

Herein, in the case that E.sup.1 is single bond, leaving group A.sup.3 represents halogen such as chlorine, bromine, iodine, etc. and in the case that E.sup.1 is --CO--, A.sup.3 -El-Q represents HOOC-Q (A.sup.3 is OH) or a carboxylic acid reactive derivative. The carboxylic acid reactive derivative includes an acid halide (acid chloride, acid bromide, etc.), an acid anhydride (acid anhydride formed with a dehydrating condensing agent such as N, N'-dicyclohexylcarbodiimide, etc., in the reaction system, commercially available acid anhydrides, etc.), an activated ester (p-nitrophenyl ester, N-hydroxysuccinimide ester, etc.), a mixed acid anhydride (monoethyl carbonate, monoisobutyl carbonate, etc.) and the like. Further in the case that E.sup.1 is --COO--, A.sup.3 represents halogen as described above and in the case that E.sup.1 is --SO.sub.2 --, A.sup.3 represents halogen or --O--SO.sub.2 --Q.

Compound (Ic) can be obtained by reacting Compound (XII) or acid addition salts thereof with 1 to 5 molar equivalents of Compound (XIII), either in an inert solvent such as methylene chloride, chloroform, etc., in the presence of a base such as pyridine, etc., or in a basic organic solvent such as pyridine or triethylamine, etc., at a temperature of 0.degree. C. to room temperature for 1 to 24 hours.

METHOD 4-1

Synthesis of Compound (Id) in Compound (I), wherein M is --COOH ##STR38## wherein one of R.sup.A1 and R.sup.B1 represents --Y--COOH and the other represents hydrogen; and , X.sub.1 --X.sub.2, G.sup.A, G.sup.B, W, Z, Y, n, g.sup.A, g.sup.B and p have the same significances as described above.

Compound (Id) can be obtained by hydrolysis of the corresponding carboxylic acid ester.

That is, Compound (Id) can be obtained by subjecting Compound (Ie) [in Compound (I), compound wherein M is --COOR.sup.3c (wherein R.sup.3c represents lower alkyl in the definitions for R.sup.3 described above)] synthesized according to Methods 1 to 3, to an appropriate hydrolysis method, for example, by reacting with a molar equivalent to an excess of sodium hydroxide or potassium hydroxide, etc. in a solvent mixture of a lower alcohol such as methanol, ethanol, etc. and water, at a temperature of from room temperature to the boiling point of the solvent for 1 to 48 hours.

METHOD 4-2

Synthesis of Compound (Id-1) in Compound (I), wherein Y is single bond ##STR39## wherein one of R.sup.A2 and R.sup.B2 represents --COOH and the other represents hydrogen; and , X.sub.1 --X.sub.2, G.sup.A, G.sup.B, W, Z, n, g.sup.A, g.sup.B and p have the same significances as described above. Compound (Id-1) can be obtained according to the following reaction steps: ##STR40## wherein one of Hal.sup.A and Hal.sup.B represents Hal and the other represents hydrogen; and , X.sub.1 --X.sub.2, R.sup.A2, R.sup.B2, G.sup.A, G.sup.B, W, Z, Hal, n, g.sup.A, g.sup.B and p have the same significances as described above.

Compound (Id-1) can be obtained by carboxylating Compound (XIV) synthesized from Compound (II-1) in a manner similar to Methods 1 to 3.

Carboxylation can be performed by reacting, for example, Compound (XIV) with 1 molar equivalent of a metallizing agent, e.g., n-butyl lithium, in an inert solvent such as tetrahydrofuran, etc., at a temperature of from -78.degree. C. to room temperature, for 10 minutes to 12 hours followed by reacting the resulting reaction mixture with 1 molar equivalent to a largely excessive amount of carbon dioxide at a temperature of from -78.degree. C. to room temperature, for 10 minutes to 12 hours. Alternatively, Compound (Id-1) can be obtained by preparing the corresponding Grignard reagent from Compound (XIV) and magnesium in an inert solvent such as diethyl ether, etc. in a manner similar to Method 2-2 and reacting the reagent with carbon dioxide, and the like method.

METHOD 5

In the methods for production shown by Methods 1 through 4, where groups defined in Compound (I) change under reaction conditions for practicing the method or are inappropriate for practicing the method, the groups may be subjected to conventional means used in organic synthesis chemistry, for example, means for protecting functional groups, means for removing protection, etc. [for example, cf., Green, Protective Groups in Organic Synthesis, John Wiley & Sons Incorporated (1981)], methods for oxidation, reduction, hydrolysis, etc. [for example, cf., SHIN-JIKKEN KAGAKU KOZA, vols. 14 & 15, Maruzen (1977)].

For example, in case that group M is --COOH, 4,4-dimethyloxazoline, etc. are preferably used as a protecting group for --COOH (for example, Japanese Published Unexamined Patent Application No. 10784/1988) in the method in which the corresponding ester is hydrolyzed (cf. Method 4-1 described above) or in the reaction using a Grignard reagent (cf., for example, Method 2-2). Further, a desired compound can be obtained by hydrolyzing (removing a protecting group in) a compound obtained by Methods 1 through 4, etc. in which group --Y--M is --Y'--CH.sub.2 OR.sup.10 [wherein Y' represents a group obtained by removing CH.sub.2 from Y and represents a protecting group for hydroxyl (e.g., acetyl, tetrahydropyranyl, etc.)] to convert into --Y'--CH.sub.2 OH and oxidizing the compound.

The intermediates and objective compounds in the respective methods described above can be isolated and purified by purification methods conventionally used in organic synthesis chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various column chromatographies, etc. Further the intermediates may also be provided in the subsequent reaction, without being particularly purified.

In Compound (I) obtained by the foregoing methods, compounds wherein W is shown by .dbd.CH-- include geometrical isomers of E-form and Z-form with respect to stereochemistry. In general, the methods described above give a mixture of these isomers. Isolation and purification-of these isomers can be made in a conventional manner in organic synthesis chemistry, for example, column chromatography, recrystallization, etc. It is also possible to isolate the isomers at stages of intermediates (Xa to Xe) by the various methods described above.

Further, if desired, E- and Z-forms may be isomerized from each other. This can be made by treating each isomer under reflux in, e.g., acetic acid, for 1 to 24 hours, in the presence of an appropriate acid catalyst such as p-toluenesulfonic acid, etc.

In the present invention, Compound (I) includes not only the E/Z isomers described above but also all possible stereoisomers and a mixture thereof.

When the synthesis yields Compound (I) in the form of a salt and such salt is a desired product, the thus formed compound (I) may be purified as is.

When Compound (I) is obtained in a free form, salts may be formed in a conventional manner. Furthermore, Compound (I) and pharmaceutically acceptable salts thereof may also be present in the form of addition products to water or various solvents; these adducts including the pharmaceutically acceptable salts are also included in the present invention.

Specific examples of Compound (I) obtained by various methods are shown in Table 1.

Numbering of substitution positions in Table 1 and Table 6 later described does not necessarily harmonize with the correct nomenclature [cf. see (NOTE) below]; but for purpose of simplicity, numbering of the substitution positions is systematically made as illustrated below. ##STR41##

NOTE

In cycloheptene derivatives (wherein X.sub.1 --X.sub.2 is --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--), despite the positional number in the general formula above, for example, a substituent on the carbon at the 2-position in the formula above is correctly given as a substituent at the 3-position. However, in the tables, according to the positional numbering in the formula described above, --COOH on the carbon at the 2-position is indicated to be 2--COOH (correctly 3--COOH).

                                      TABLE 1
    __________________________________________________________________________
     ##STR42##
     X.sub.1X.sub.2
            ##STR43##                          R.sup.A /R.sup.B
                                                          No.poundCom-
    __________________________________________________________________________
    CH.sub.2 O
            ##STR44##                         2-COOCH.sub.3 2-COOH
                                                         1a 1b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         2a
                                              2-CH.sub. 2 COOH
                                                         2b
    "      "                                  2-CH.sub.2 CH.sub.2 COOCH.sub.3
                                                         3a
                                              2-CH.sub.2 CH.sub.2 COOH
                                                         3b
    "      "                                  2-CH(CH.sub.3)COOCH.sub.3
                                                         4a
                                              2-CH(CH.sub.3)COOH
                                                         4b
    "      "
                                               ##STR45## 5
    "      "                                  3-COOCH.sub.3
                                                         6a
                                              3-COOH     6b
    "      "                                  9-COOCH.sub.3
                                                         7a
                                              9-COOH     7b
            ##STR46##                         2-COOCH.sub.3 2-COOH
                                                         8a 8b
    "
            ##STR47##                         2-COOCH.sub.3 2-COOH
                                                         9a 9b
    CH.sub.2 O
            ##STR48##                         2-COOCH.sub.3 2-COOH
                                                         10a 10b
    "
            ##STR49##                         2-COOCH.sub.3 2-COOH
                                                         11a 11b
    "
            ##STR50##                         2-COOCH.sub.3 2-COOH
                                                         12a 12b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         13a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         13b
    "
            ##STR51##                         2-COOCH.sub.3 2-COOH
                                                         14a 14b
    "
            ##STR52##                         2-COOCH.sub.3 2-COOH
                                                         15a 15b
    "
            ##STR53##                         2-COOCH.sub.3 2-COOH
                                                         16a 16b
    "
            ##STR54##                         2-COOCH.sub.3 2-COOH
                                                         17a 17b
    "
            ##STR55##                         2-COOCH.sub.3 2-COOH
                                                         18a 18b
    "
            ##STR56##                         2-COOCH.sub.3 2-COOH
                                                         19a 19b
    "
            ##STR57##                         2-COOCH.sub.3 2-COOH
                                                         20a 20b
    CH.sub.2 O
            ##STR58##                         2-COOCH.sub.3 2-COOH
                                                         21a 21b
    "
            ##STR59##                         2-COOCH.sub.3  2-COOH
                                                         22a 22b
    "
            ##STR60##                         2-COOCH.sub.3 2-COOH
                                                         23a 23b
    "
            ##STR61##                         2-COOCH.sub.3 2-COOH
                                                         24a 24b
    "
            ##STR62##                         2-COOCH.sub.3 2-COOH
                                                         25a 25b
    "
            ##STR63##                         2-COOCH.sub.3 2-COOH
                                                         26a 26b
    "
            ##STR64##                         2-COOCH.sub.3 2-COOH
                                                         27a 27b
    "
            ##STR65##                         2-COOCH.sub.3 2-COOH
                                                         28a 28b
    "
            ##STR66##                         2-COOCH.sub.3 2-COOH
                                                         29a 29b
    "
            ##STR67##                         2-COOCH.sub.3 2-COOH
                                                         30a 30b
    "
            ##STR68##                         2-COOCH.sub.3 2-COOH
                                                         31a 31b
    "
            ##STR69##                         2-COOCH.sub.3 2-COOH
                                                         32a 32b
    CH.sub.2 O
            ##STR70##                         2-COOCH.sub.3 2-COOH
                                                         33a 33b
    "
            ##STR71##                         2-COOCH.sub.3 2-COOH
                                                         34a 34b
    "
            ##STR72##                         2-COOCH.sub.3 2-COOH
                                                         35a 35b
    "
            ##STR73##                         2-COOCH.sub.3 2-COOH
                                                         36a 36b
    "
            ##STR74##                         2-COOCH.sub.3 2-COOH
                                                         37a 37b
    "
            ##STR75##                         2-COOCH.sub.3 2-COOH
                                                         38a 38b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         39a
                                              2-CH.sub.2 COOH
                                                         39b
    "      "                                  2-CH(CH.sub.3)COOCH.sub.3
                                                         40a
                                              2-CH(CH.sub.3)COOCH.sub.
                                                         40b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         41a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         41b
    "      "                                  2-CH.sub.2 CH.sub.2 COOCH.sub.3
                                                         42a
                                              2-CH.sub.2 CH.sub.2 COOH
                                                         42b
    "
            ##STR76##                         2-COOCH.sub.3 2-COOH
                                                         43a 43b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         44a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         44b
    CH.sub.2 O
            ##STR77##                         2-COOCH.sub.3 2-COOH
                                                         45a 45b
    "
            ##STR78##                         2-COOCH.sub.3 2-COOH
                                                         46a 46b
    "
            ##STR79##                         2-COOCH.sub.3 2-COOH
                                                         47a 47b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         48a
                                              2-CH.sub.2 COOH
                                                         48b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         49a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         49b
    "
            ##STR80##                         2-COOCH.sub.3 2-COOH
                                                         50a 50b
    "
            ##STR81##                         2-COOCH.sub.3 2-COOH
                                                         51a 51b
    "
            ##STR82##                         2-COOCH.sub.3 2-COOH
                                                         52a 52b
    "
            ##STR83##                         2-COOCH.sub.3 2-COOH
                                                         53a 53b
    "
            ##STR84##                         2-COOCH.sub.3 2-COOH
                                                         54a 54b
    "
            ##STR85##                         2-COOCH.sub.3 2-COOH
                                                         55a 55b
    "
            ##STR86##                         2-COOCH.sub.3 2-COOH
                                                         56a 56b
    CH.sub.2 O
            ##STR87##                         2-COOCH.sub.3 2-COOH
                                                         57a 57b
    "
            ##STR88##                         2-COOCH.sub.3 2-COOH
                                                         58a 58b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         59a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         59b
    "
            ##STR89##                         2-COOCH.sub.3 2-COOH
                                                         60a 60b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         61a
                                              2-CH.sub.2 COOH
                                                         61b
    "
            ##STR90##                         2-COOCH.sub.3 2-COOH
                                                         62a 62b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         63a
                                              2-CH.sub.2 COOH
                                                         63b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         64a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         64b
    "
            ##STR91##                         2-COOCH.sub.3 2-COOH
                                                         65a 65b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         66a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         66b
    "
            ##STR92##                         2-COOCH.sub.3 2-COOH
                                                         67a 67b
    CH.sub.2 O
            ##STR93##                         2-COOCH.sub.3 2-COOH
                                                         68a 68b
    "
            ##STR94##                         2-COOCH.sub.3 2-COOH
                                                         69a 69b
    "
            ##STR95##                         2-COOCH.sub.3 2-COOH
                                                         70a 70b
    "
            ##STR96##                         2-COOCH.sub.3 2-COOH
                                                         71a 71b
    "
            ##STR97##                         2-COOCH.sub.3 2-COOH
                                                         72a 72b
    "
            ##STR98##                         2-COOCH.sub.3 2-COOH
                                                         73a 73b
    "
            ##STR99##                         2-COOCH.sub.3 2-COOH
                                                         74a 74b
    "
            ##STR100##                        2-COOCH.sub.3 2-COOH
                                                         75a 75b
    "
            ##STR101##                        2-COOCH.sub.3 2-COOH
                                                         76a 76b
    "
            ##STR102##                        2-COOCH.sub.3 2-COOH
                                                         77a 77b
    "
            ##STR103##                        2-COOCH.sub.3 2-COOH
                                                         78a 78b
    "
            ##STR104##                        2-COOCH.sub.3 2-COOH
                                                         79a 79b
    CH.sub.2 O
            ##STR105##                        2-CH.sub.2 COOCH.sub.3 2-CH.sub.
                                              2 COOH     80a 80b
    "      "                                  2-CH(CH.sub.3)COOCH.sub.3
                                                         81a
                                              2-CH(CH.sub.3)COOH
                                                         81b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         82a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         82b
    "      "                                  2-CH.sub.2 CH.sub.2 COOCH.sub.3
                                                         83a
                                              2-CH.sub.2 CH.sub.2 COOH
                                                         83b
    "
            ##STR106##                        2-COOCH.sub.3 2-COOH
                                                         84a 84b
    "
            ##STR107##                        2-COOCH.sub.3 2-COOH
                                                         85a 85b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         86a
                                              2-CH.sub.2 COOH
                                                         86b
    "      "                                  2-CH(CH.sub.3)COOCH.sub.3
                                                         87a
                                              2-CH(CH.sub.3)COOH
                                                         87b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         88a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         88b
    "      "                                  2-CH.sub.2 CH.sub.2 COOCH.sub.3
                                                         89a
                                              2-CH.sub.2 CH.sub.2 COOH
                                                         89b
    "
            ##STR108##                        2-COOCH.sub.3 2-COOH
                                                         90a 90b
    "      "                                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                                                         91a
                                              2-C(CH.sub.3).sub.2 COOH
                                                         91b
    "
            ##STR109##                        2-COOCH.sub.3 2-COOH
                                                         92a 92b
    CH.sub.2 O
            ##STR110##                        2-COOCH.sub.3 2-COOH
                                                         93a 93b
    "
            ##STR111##                        2-COOCH.sub.3 2-COOH
                                                         94a 94b
    "
            ##STR112##                        2-COOCH.sub.3 2-COOH
                                                         95a 95b



    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         96a
                                              2-CH.sub.2 COOH
                                                         96b
    "
            ##STR113##                        2-COOCH.sub.3 2-COOH
                                                         97a 97b
    "      "                                  2-CH.sub.2 COOCH.sub.3
                                                         98a
                                              2-CH.sub.2 COOH
                                                         98b
    CH.sub.2 S
            ##STR114##                        2-COOCH.sub.3 2-COOH
                                                         99a 99b
    "
            ##STR115##                        2-COOCH.sub.3 2-COOH
                                                         100a 100b
    CH.sub.2 CH.sub. 2
            ##STR116##                        2-COOCH.sub.3 2-COOH
                                                         101a 101b
    "
            ##STR117##                        2-COOCH.sub.3 2-COOH
                                                         102a 102b
    CHCH
            ##STR118##                        2-COOCH.sub.3 2-COOH
                                                         103a 103b
    "
            ##STR119##                        2-COOCH.sub.3 2-COOH
                                                         104a 104b
    __________________________________________________________________________

The thus prepared compound (I) exhibit a potent TXA.sub.2 antagonizing activity and some of them also possess an antiallergic activity and/or antihistaminic activity. Preferred examples of Compound (I) are shown in Table 2.

Names of the compounds given Table 2, reference examples and examples later described are indicated by correct nomenclature.

                  TABLE 2
    ______________________________________
    Compound                     No.
    ______________________________________
    11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11-
                                  1b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11-
                                  2b
    dihydrodibenz[b,e]oxepin-2-acetic acid
    11-[2-(4-Benzyl-1-piperazinyl)ethyl]thio-6,11-
                                 11b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[2-(4-Chlorobenzyl-1-piperazinyl)ethyl]thio-6,11-
                                 12b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    2-Methyl-2-[11-[2-(4-chlorobenzyl-1-piperazinyl)-
                                 13b
    ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    11[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]-
                                 17b
    ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-
    carboxylic acid
    11-[2-(4-Benzyl-1-homopiperazinyl)ethyl]thio-6,11-
                                 32b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[2-(4-Phenyl-1-piperidinyl)ethyl]thio-6,11-
                                 37b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-
                                 38b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-
                                 39b
    dihydrodibenz[b,e]oxepin-2-acetic acid
    2-Methyl-2-[11-[2-(4-benzyl-1-piperidinyl)-
                                 41b
    ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    11-[2-[4-(4-Chlorobenzyl)-1-piperidinyl]ethyl]thio-6,11-
                                 43b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    2-Methyl-2-[11-[2-[4-(4-chlorobenzyl-1-piperidinyl)-
                                 44b
    ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-
                                 47b
    ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-
    carboxylic acid
    11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-
                                 48b
    ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-
    acetic acid
    2-Methyl-2-[11-[2-[4-[2(3H)-benzimidazolon-1-yl]-
                                 49b
    piperidino]ethyl]thio-6,11-dihydrodibenz[b,e]-
    oxepin-2-carboxylic acid
    11-[2-[1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-on-
                                 58b
    8-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-
    2-carboxylic acid
    2-Methyl-2-[11-[2-[1-phenyl-1,3,8-triazaspiro[4.5]-
                                 59b
    decan-4-one-8-yl]ethyl]thio-6,11-dihydrodibenz-
    [b,e]oxepin-2-yl]propionic acid
    11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-
                                 62b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-
                                 63b
    dihydrodibenz[b,e]oxepin-2-acetic acid
    2-Methyl-2-[11-[3-(4-benzyl-1-piperazinyl)propylidene-
                                 64b
    6,11-dihydrodibenz[b,e]oxepin-2-yl]propionic acid
    11-[3-[4-(4-Chlorobenzyl-1-piperazinyl)propylidene]-
                                 65b
    6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid
    2-Methyl-2-[11-[3-[4-(4-chlorobenzyl-1-piperazinyl)-
                                 66b
    propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    11-[2-[4-(4-Thienylsulfonyl)-1-piperazinyl]-
                                 79b
    ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic
    acid
    11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]-
                                 80b
    ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic
    acid
    2-[11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]-
                                 81b
    ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    2-Methyl-2-[11-[2-[4-(2-thienylsulfonyl-1-
                                 82b
    piperazinyl)ethylidene-6,11-dihydrodibenz[b,e]oxepin-
    2-yl]propionic acid
    3-[11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl)-
                                 83b
    ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    11-[3-(4-Phenyl-1-piperidinyl)propylidene]-6,11-
                                 84b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11-
                                 85b
    dihydrodibenz[b,e]oxepin-2-carboxylic acid
    11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11-
                                 86b
    dihydrodibenz[b,e]oxepin-2-acetic acid
    2-Methyl-2-[11-[3-(4-benzyl-1-piperidinyl)-
                                 88b
    propylidene]-6,11-dihydrodibenz[b,e] oxepin-2-yl]-
    propionic acid
    11-[3-[4-(4-Chlorobenzyl)-1-piperidinyl]propylidene]-
                                 90b
    6,11-dihydrodibenz[b,e]oxepin-2-acetic acid
    2-Methyl-2-[11-[3-[4-(4-chlorobenzyl-1-piperidinyl)-
                                 91b
    propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-
    propionic acid
    11-[3-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-
                                 93b
    propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic
    acid
    11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-
                                 98b
    ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic
    acid
    11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-
                                 99b
    dihydrodibenzo[b,e]thiepin-2-carboxylic acid
    11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11-
                                 100b
    dihydrodibenzo[b,e]thiepin-2-carboxylic acid
    5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10,11-
                                 101b
    dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid
    5-[2-[4-(2-Thienyl)sulfonyl-1-piperidinyl)ethylidene]-
                                 102b
    10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic
    acid
    5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5H-dibenzo-
                                 103b
    [a,d]cyclohepten-3-carboxylic acid
    5-[2-[4-(2-Thienyl)sulfonyl-1-piperidinyl)ethylidene]-
                                 104b
    5H-dibenzo[a,d]cyclohepten-3-carboxylic acid
    ______________________________________

Next, TXA.sub.2 antagonizing activity of Compound (I) is described below.

Test on anti-platelet activity (TXA.sub.2 antagonizing test

Using guinea pig platelets, influence of the compounds in accordance with the present invention on platelet aggregation induced by U-46619 (9,11-dideoxy-9.alpha.,11a-metanoepoxyprostaglandin F.sub.2 .alpha.; manufactured by Cayman Chemica Co., Ltd.) which is a TXA.sub.2 /prostaglandin H.sub.2 receptor stimulant was examined

Male guinea pig (Hartley strain; body weight, 300 to 600 g) was anesthesized by intraperitoneal administration of sodium pentobarbital (30 mg/kg) and blood was collected from the descending aorta of the abdomen with a 1/10 volume of sodium citrate. By centrifugation (KC-70: manufactured by Kubota Co., Ltd.) at 800 rpm for 10 minutes, platelet rich plasma (PRP) was collected. Platelet aggregation induced by U-46619 (0.5-1 .mu.M) was determined by photometry [Born, G.V.R. et al., Nature (London), 194, 927-929 (1962)]. A test compound was pretreated 3 minutes prior to aggregation induction and an ability of inhibiting aggregation was measured. The minimum concentration for inhibiting platelet aggregation by 30% or more was defined as the minimum effective concentration (MEC) of the test compound.

The results are shown in Table 3.

Antiallergic activity test

Antiallergic activity was examined in accordance with the passive cutaneous anaphylaxis (PCA) test using rats. As test animals, Wistar strain male rats weighing 180 to 220 g were used to collect antiserum and for the PCA test, Wistar strain male rats weighing 120 to 140 g were used.

A) Preparation of anti-egg white albumin (EWA) rat serum

Anti-EWA rat serum was prepared according to the method of Stotland and Share [Can. J. Physiol. Pharmacol., 52, 1114 (1974)]. That is, 1 mg of EWA was mixed with 20 mg of aluminum hydroxide gel and 0.5 ml of pertussis-diphtheria-tetanus mixed vaccine. The mixture was subcutaneously administered to the rat paw in 4 portions. Fourteen days after, blood was collected from the carotid artery and the serum was isolated and stored in a state frozen at -80.degree. C. Titer of this antiserum to homologous PCA for 48 hours was 1:32.

B) Homologous PCA test for 48 hours using rats

Three rats were used per group. After the hair at the back was cut, 0.05 ml each of anti-EWA rat serum diluted to 8-fold with physiological saline was intracutaneously injected to each rat at the back in 2 places to passively sensitize the rat. A test compound or its solution (physiological saline solution or CMC solution) was orally administered 47 hours after and 0.5 ml/100 g of 1% Evans Blue physiological saline containing 2 mg of antigen EWA was then intravenously administered to the tail vein an hour after the administration. Thirty minutes later, the animal was bled to death. The skin was peeled off and a leaked dye amount at the blue dyed portion was measured according to the method of Katayama et al. [Microbiol. Immunol., 22, 89 (1978)]. That is, the blue dyed portion was cut off with scissors, put into a test tube charged with 1 ml of 1 N potassium hydroxide and incubated at 37.degree. C. for 24 hours. After 9 ml of a mixture of 0.6 N phosphate:acetone (5:13) was added to the system, the mixture was shaken followed by centrifugation at 2500 rpm for 10 minutes. The absorbancy of the supernatant at 620 nm was measured and the leaked dye amount was quantitatively determined by comparison with a calibration, curve previously prepared. A value of one rat was obtained from a mean value of the two portions and an inhibition rate of each rat was calculated according to the following equation. ##EQU1##

The case showing that the inhibition rate is 50% or more is judged to be positive in the PCA inhibition activity and the minimum dose in which at least one out of 3 rats was recognized to be positive was defined as the minimum effective dose (MED) of the test compound.

The results are shown in Table 3.

Acute toxicity test

Using three dd strain male mice weighing 20.+-.1 g, a test compound was orally (po; 300 mg/kg) or intraperitoneally (ip; 100 mg/kg) administered. MLD (the minimum lethal dose) was determined by observing the mortality for seven days after administration.

The results are shown in Table 3.

                  TABLE 3
    ______________________________________
            Acute Toxicity
                         Antiallergic
                                     TXA.sub.2
            (MLD)        Activity    Antagonizing
    Compound
            mg/kg        (MED) mg/kg Activity (MEC)
    No.**   po      ip       po        .mu.g/ml
    ______________________________________
      1b'   >300    >100       10      3
     8b     >300    >100       10      1
      9b'   >300    >100       10      1
    11b     >300    >100       10      1
    25b     >300    >100       10      3
    37b     >300    >100       1       10
    38b     >300    >100       1       1
    E-73b   >300    >100     >100      10
     E-75b' >300    >100      100      0.1
    E-78b   >300    >100     >100      3
    E-79b   >300    >100     >100      30
    BM13177*
            >300    >100     >100      3
    (reference
    compound)
    ______________________________________
     ##STR120##
     **In Compound No., symbol ' indicates an addition product of the
     corresponding compound in Tables 1 through 2 to a salt or solvent and,
     symbols E and Z represents Eform and Zform, respectively (the same shall
     apply hereinafter).

As demonstrated in Table 3, Compound (I) and pharmaceutically acceptable salts thereof possess an excellent TXA.sub.2 antagonizing activity and some compounds also possess an antiallergic activity.

Binding study using .sup.3 H-U46619 (TXA.sub.2 receptor binding activities test)

Receptor binding was determined by a modified method of Kattelman et al. [Thrombosis Research, 41, 471 (1986)].

To a washed platelet suspension (1.times.10.sup.8 platelets) of guinea pig were added 12 nM of tritium-labeled U46619 (.sup.3 H-U46619; NEN Co., Ltd.) and a test compound (final concentration: 1 .mu.M) solution. After keeping at 37.degree. C. for 20 minutes, the mixture was rapidly filtered through a glass fiber filter paper (GF/C; Whatman). Immediately, the filter paper was washed 5 times with 3 ml of ice-cold 50 mM Tris-hydroxymethylaminomethane buffer (containing 100 mM sodium chloride). The glass fiber filter was transferred to a vial and a scintillator (Ex-H; manufactured by Wako Pure Chemical Industries Co., Ltd.) was added thereto. The radioactivity was determined with a liquid scintillation counter.

It is already known that .sup.3 H-U46619 is capable of binding with TXA.sub.2 receptor (see the publication supra). An inhibitory activity of the test compound against this binding means an ability of binding with the TXA.sub.2 receptor. It is also known that a good relationship exists between this binding activity and the anti-platelet activity (TXA.sub.2 antagonizing test).

An inhibitory activity (binding activity) of the test compound was calculated by the following equation. ##EQU2##

Notes

Amount of the total binding is an amount of .sup.3 H-U46619-bound radioactivity in the absence of a test compound.

The amount of non-specific binding is used to mean an amount of .sup.3 H-U46619-bound radioactivity in the presence of 10 .mu.M U-46619.

The amount bound in the presence of a test compound is an amount of .sup.3 H-U46619-bound radioactivity in the presence of a test compound in various concentrations.

The results are shown in Table 4.

                  TABLE 4
    ______________________________________
    Compound
    No.                       % Inhibition
    ______________________________________
    11b                       70
    25b                       78
    38b                       81
    E-73b                     85
    E-75b'                    85
    E-78b                     83
    E-79b                     77
    Reference compounds:
    Ketotifen                 -3
    BM13177                   31
     ##STR121##               -4
     ##STR122##                1
    ______________________________________

As demonstrated in Table 4, Compound (I) and pharmaceutically acceptable salt thereof have an excellent binding ability to TXA.sub.2 receptor.

This inhibitory activity is not observed with hitherto known antiallergic agents, for example, Ketotifen [Merck Index, 10th edition, page 762 (1983)] and known antiallergic agents such as Compound (A) Japanese Published Unexamined Patent Application No. 28972/1985) and Compound (B) (Japanese Published Unexamined Patent Application No. 10784/1988); one of excellent activity of Compound (I) is TXA.sub.2 receptor binding ability.

Binding study using .sup.3 H-Pyrilamine (Histamine H.sub.1 receptor binding)

Receptor binding was determined by the method of Chang et al. [J. Neurochem., 32, 1953 (1979)].

The cerebellum of guinea pig was suspended in a 40-fold amount (V/W) of chilled 50 mM phosphate buffer (pH 7.5) with Polytron Homogenizer (Kinematica Co., Ltd.). The suspension was centrifuged (35,500.times.g, 10 minutes). The resulting precipitates were resuspended in an equal amount of fresh buffer followed by centrifugation. A 100-fold amount (V/W) of chilled buffer was added to the final precipitates.

To 1 ml of the membrane suspension adjusted as described above were added 50 .mu.l of tritium-labeled pyrilamine (.sup.3 H-pyrilamine; NEN Co., Ltd.) and 50 .mu.l of a test compound. The mixture was allowed to stand at 25.degree. C. for 30 minutes, 4 ml of chilled buffer was added thereto. The mixture was rapidly filtered through a glass fiber filter (GF/C; Whatman). The filter paper was further washed three times with 5 ml of buffer. Hereafter procedures were performed in a manner similar to the TXA.sub.2 receptor binding test to determine radioactivity.

An inhibitory activity of the test compound against H.sub.1 receptor was calculated by the following equation. ##EQU3##

Notes

Amount of the total binding is an amount of .sup.3 H-pyrilamine-bound radioactivity in the absence of a test compound.

The amount of non-specific binding is an amount of .sup.3 H-pyrilamine-bound radioactivity in the presence of 3 .mu.M Astemizole (manufactured by Janesen Pharmaceutica).

The amount bound in the presence of a test compound is an amount of .sup.3 H-pyrilamine-bound radioactivity in the presence of a test compound in various concentrations.

Inhibitory activity of the test compounds at 10.sup.-6 M are shown in table 5.

                  TABLE 5
    ______________________________________
    Compound
    No.               (%) Inhibition
    ______________________________________
     1b'              68
    11b               95
    25b               95
    38b               92
    Reference Compounds:
    Ketotifen         100
    BM13177            0
    Compound A        88
    ______________________________________

Compound (I) and pharmaceutically acceptable salts thereof may be administered alone but in general, it is preferably administered as a combination medical preparation. These medical preparations are used for animal and human beings.

The medical preparation in accordance with the present invention may contain, as an active ingredient, Compound (I) or pharmaceutically acceptable salts thereof singly or as admixture with other optional effective components for different treatment. Further these medical preparations can be produced by optional procedures well known in the pharmaceutical field, by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.

Herein, as the optional effective components for different treatment combined with Compound (I) or pharmaceutically acceptable salts thereof, mention may be made of, for example, a steroid, a non-steroid antiinflammatory agent, a peripheral analgesic, a leucotriene antagonist, a leucotriene biosynthesis inhibitor, an H.sub.2 receptor antagonist, an antihistaminic agent, a histamine release inhibitor, a bronchodilator, an angiotensin converting enzyme inhibitor, a thromboxane A.sub.2 biosynthesis inhibitor, an H.sup.+ -K.sup.+ ATPase inhibitor, a coronary dilator, a calcium antagonist, a diuretic, a xanthine oxidase inhibitor, a cerebral circulation improving agent, a celebral metabolism activator, a cerebral protecting agent, a liver protecting agent, an antiplatelet agent, a thrombolytic agent, an adrenaline .alpha. receptor antagonist, an adrenergic .beta. receptor agent, an adrenaline .beta. receptor antagonist, a serotonine antagonist, a platelet activation factor (PAF) antagonist, an adenosine receptor antagonist, an antihyperlipidemic agent, a cholesterol biosynthesis inhibitor, an immunostimulating agent, an immunosuppressive agent, an anticancer agent, etc.

It is preferred that the most effective route for treatment be selected as a route for administration. Oral or parenteral administration such as intrarectal, topical, intranasal, intraocular, intrabuccal, subcutaneous, intramuscular and intravenous routes, etc. are mentioned.

As the form of administration, preparations of the invention may be administered as a capsule, a tablet, a granule, a powder, a syrup, an emulsion, a suppository, an ointment, an eyedrop, a nosedrop, a troche, an aerosol, an injection, etc.

A liquid preparation suited for oral administration, for example, an emulsion and a syrup can be prepared using water; sugars such as sucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol, propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil, etc.; antiseptics such as a p-hydroxybenzoic acid ester, etc.; flavors such as strawberry flavor, pepper mint, etc. Further a capsule, a tablet, a powder and a granule, etc. can be prepared using an excipient such as lactose, glucose, sucrose, mannitol, etc.; a disintegrator such as starch, sodium alginate, etc.; a lubricant such as magnesium stearate, talc, etc.; a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, etc.; a surfactant such as an aliphatic ester, etc.; a plasticizer such as glycerine, etc.

A preparation suited for parenteral administration is composed of a sterile aqueous preparation containing active compounds which are preferably isotonic to the blood of recipient. For example, with an injection, a solution for injection is prepared using carriers composed of a saline solution, a glucose solution or a mixture of saline water and glucose solution.

A nasal spray preparation is composed of a purified aqueous solution of the active compounds which contains an antiseptic and an isotonic agent. Such a preparation is adjusted to pH compatible with the nasal membrane and to an isotonic state.

An ocular preparation is prepared in a manner similar to the nasal spray, except that pH and isotonic factors are controlled so as to fit those of eyes.

A topical preparation is prepared by dissolving or suspending the active compound in one or more media, for example, a mineral oil, petroleum, a polyvalent alcohol or other bases used for topical medical preparations.

A preparation for rectal administration is provided as a suppository using conventional carriers, for example, cacao fat, hydrogenated fat or hydrogenated fat carboxylic acid, etc.

Further these parenteral preparations may also be added with one or more auxiliary components such as a diluent, a fragrance, an antiseptic (including an antioxidant), an excipient, a disintegrator, a lubricant, a binder, a surfactant, a plasticizer and the like.

Effective dose and regimen of administration of Compound (I) or pharmaceutically acceptable salts thereof vary depending upon mode of administration, age and body weight of the patient and properties or severity of conditions to be treated. In general, daily dose is 0.01 to 1,000 mg/person

Hereafter, the present invention is described by referring to Reference Examples and Examples below.

Intermediates obtained in the following Reference Examples are shown in Table 6.

                                      TABLE 6
    __________________________________________________________________________
     ##STR123##
    Compound
    (Reference
    Example)
          X.sub.1X.sub.2
                  R.sup.o    X.sup.o
    __________________________________________________________________________
    a (1) CH.sub.2 O
                  2-COOCH.sub.3
                            O
    b (2) "       "         OH
    c (3) "       "         CHCH.sub.2 Cl
    d (4) "       2-CH.sub.2 COOCH.sub.3
                            O
    e (5) "       "         CHCH.sub.2 Cl
    f (6) "       2-C(CH.sub.3).sub.2 COOCH.sub.3
                            O
    g (7) "       "         OH
    h (8) "       2-COOCH.sub.3
                             ##STR124##
    i (9) "       "
                             ##STR125##
    j (10)
          "       "
                             ##STR126##
    k (11)
          "       "
                             ##STR127##
    l (12)
          "       2-C(CH.sub.3).sub.2 COOCH.sub.3
                             ##STR128##
    m (13)
          CH.sub.2 O
                  2-C(CH.sub.3).sub.2 COOCH.sub.3
                             ##STR129##
    n (14)
          "       "
                             ##STR130##
    o (15)
          CH.sub.2CH.sub.2
                  2-COOCH.sub.3
                             ##STR131##
    p (16)
          "       "
                             ##STR132##
    q (17)
          CHCH    "
                             ##STR133##
    r (18)
          "       "
                             ##STR134##
    s (19)
          CH.sub.2 O
                  "
                             ##STR135##
    t (20)
          "       "         CHCH.sub.2 CH.sub.2 OSO.sub.2 CH.sub.3
    u (21)
          "       "
                             ##STR136##
    __________________________________________________________________________

REFERENCE EXAMPLE 1

Methyl 11-oxo-6,11-dihydrodibenz[b,3]oxepin-2-carboxylate (Compound a):

A mixture of 348.9 g of methyl p-hydroxybenzoate sodium salt, 402.4 g of phthalide and 200 g of sodium chloride was stirred at 150.degree. C. for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 4 liters of 10% acetic acid aqueous solution were added thereto. The mixture was allowed to stand at room temperature overnight. After stirring at room temperature for 3 hours, crystals were recovered by filtration. To the crystals was added 6 liters of water. After stirring at room temperature for 30 minutes, the crystals were taken out by filtration. To the crystals was added 3 liters of toluene. The mixture was stirred at room temperature for an hour. The crystals were taken out by filtration and dried by heating under reduced pressure to give 393.9 g of 2-(4-methoxycarbonylphenoxy)methyl benzoate.

IR (IBr tablet, cm.sup.-1): 3400, 1700, 1610, 1260, 1235

In 5.0 liters of methylene chloride was suspended 392.7 g of the thus obtained 2-(4-methyoxycarbonylphenoxy)methyl benzoate and, 266.0 g of trifluoroacetic anhydride was added to the suspension. After stirring at room temperature for an hour, 19.4 g of boron trifluoride ethyl ether complex was added to the mixture followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water. After fractionation, the organic phase was washed with a diluted sodium hydroxide aqueous solution and then with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was recrystallized from isopropyl ether to obtain 335.3 g of the objective compound as white crystals.

Melting point: 128.degree.-129.degree. C.

    ______________________________________
    Elemental analysis: as C.sub.16 H.sub.12 O.sub.4
                    C    H
    ______________________________________
    Found (%)         71.55  4.48
    Calcd. (%)        71.63  4.51
    ______________________________________

NMR (CDCl.sub.3, .delta., ppm): 3.84(s, 3H), 5.14(s, 2H), 6.87-8.93(m, 7H)

IR (KBr tablet, cm.sup.-1): 1710, 1650, 1610, 1250, 1010

REFERENCE EXAMPLE 2

Methyl 11-hydroxy-6,11-dihydrobibenz[b,3]oxepin-2-carboxylate (Compound b):

Compound a, 50 g, obtained n Reference Example 1 was suspended in 300 ml of methanol and 6.3 g of sodium borohydride was added to the suspension. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, 10 ml of acetic acid and 300 ml of water were added thereto followed by stirring for 30 minutes. Insoluble matters were taken out by filtration and washed with methanol and then with water. By drying with heating under reduced pressure, 40 g of the objective compound was obtained.

NMR (CDCl.sub.3, .delta., ppm): 2.16(s, 6H), 2.30-2.76(m, 4H), 3.83(s, 3H), 4.83 and 6.40(ABq, J=12.6Hz, 2H), 5.01(s, lH), 6.79-7.93(m, 7H)

IR (neat, cm.sup.-1): 2950, 1710, 1240, 1015

REFERENCE EXAMPLE 3

Methyl (E)-11-(2-chloroethylidene)-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound c):

4-Methylpiperazine, 30 ml, and 74 g of paraformaldehyde were dissolved in 2 l of tetrachloroethane and 100 ml of trifluoroacetic acid was dropwise added to the solution. After stirring at 60.degree. C. for 2 hours, a solution of 36 g of methyl 11-methylene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 600 ml of tetrachloroethane was dropwise added to the reaction mixture followed by stirring at 90.degree. C. for further 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 1. Then, the mixture was washed with diethyl ether. Thereafter, 10 N sodium hydroxide aqueous solution was added to adjust pH to 13. Extraction was performed with 3 (of methylene chloride. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=5:5:1) to give 44 g of methyl 11-[2-(4-methyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2- carboxylate as colorless oil.

MS (m/z): 378 (M.sup.+)

NMR (CDCl.sub.3, .delta., ppm): 2.24(s, 3H), 2.45(s, 8H), 2.94-3.32(m, 2H), 3.84(s, 3H), 5.22(bs, 2H), 5.85 and 6.22(t, J=6.8 Hz, 1H), 6.66-8.07(m, 7H)

E-form compound, 21.5 g, isolated from the Z/E mixture described above in a conventional manner and 23.5 g of sodium acetate were suspended in 250 ml of dichloroethane and, 27.1 ml of ethyl chloroformate was dropwise added to the suspension. After completion of the dropwise addition, the mixture was stirred at room temperature for an hour and the solvent was distilled off under reduced pressure. The residue was extracted with 400 ml of ethyl acetate. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropanol to give 14.3 g of the objective compound as white crystals.

Melting point: 134.degree.-135.degree. C.

    ______________________________________
    Elemental analysis: as C.sub.18 H.sub.15 ClO.sub.3
                    C    H
    ______________________________________
    Found (%)         68.55  4.77
    Calcd. (%)        68.68  4.80
    ______________________________________

NMR (CDCl.sub.3, .delta., ppm): 3.90(s, 3H), 4.16(d, J=8.1Hz, 2H), 4.88(bs, 1H), 5.57(bs, 1H), 6.31(t, J=8.1Hz, 1H), 6.79-8.04(m, 7H)

REFERENCE EXAMPLE 4

Methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound d):

The corresponding starting material was used, treated in a manner similar to Reference Example 1 and recrystallized from methanol to give the objective compound as light yellow crystals.

Melting point: 75.degree.-76.degree. C.

REFERENCE EXAMPLE 5

Methyl (E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound e):

The corresponding starting material was used, treated in a manner similar to Reference Example 3 and recrystallized from isopropanol to give the objective compound as white crystals.

Melting point: 127.degree.-128.degree. C.

    ______________________________________
    Elemental analysis: as C.sub.19 H.sub.17 ClO.sub.3
                    C    H
    ______________________________________
    Found (%)         69.37  5.40
    Calcd. (%)        69.41  5.21
    ______________________________________

NMR (CDCl.sub.3, .delta., ppm): 3.55(s, 2H), 3.69(s, 3H), 4.14 (d, J=8.1Hz, 2H), 4.7-5.4(m, 2H), 6.23(t, J=8.1 Hz, 1H), 6.74(d, J=8.1Hz, 1H), 6.95-7.4(m, 6H)

IR (KBr tablet, cm.sup.-1): 1731, 1487, 1256, 1137, 1004

REFERENCE EXAMPLE 6

Methyl 2-methyl-2-[(11-oxo-6,11-dihydrodibenz[b,e]oxepin)-2-yl]propionate (Compound f):

Compound d, 30 g, obtained in Reference Example 4 was suspended in 300 ml of dimethylformamide and 30 g of potassium hydroxide as powder and then 27 ml of methyl iodide were added to the suspension. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was extracted with 500 ml of ethyl acetate. The extract was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) for purification to give 3.6 g of the objective compound as colorless oil.

NMR (CDCl.sub.3, .delta., ppm): 1.62(s, 6H), 3.66(s, 3H), 5.17 (s, 2H), 7.01(d, J=8.8 Hz, 1H), 7.2-7.9(m, 5H), 8.22(d, J=2.6 Hz, 1H)

IR (neat, cm.sup.-1): 2874, 1729, 1648, 1597, 1490, 1016

REFERENCE EXAMPLE 7

Methyl 2-methyl-2-[(11-hydroxy-6,11-dihydrodibenz[b,e]oxepin)-2-yl]propionate (Compound g):

The objective compound was obtained as colorless oil from Compound f obtained in Reference Example 6 in a manner similar to Reference Example 2.

NMR (CDCl.sub.3, .delta., ppm): 1.56(s, 6H), 3.62(s, 3H), 4.97 and 5.90(ABq, J=13.1Hz, 2H), 5.61(s, 1H), 6.87 (d, J=8.4 Hz, 1H), 7.05-7.40(m, 6H)

IR (neat, cm.sup.-1): 2974, 1728, 1497, 1010

REFERENCE EXAMPLE 8

Methyl 11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound h):

In 400 ml of methylene chloride was suspended 40.0 g of Compound b obtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, was added to the suspension followed by stirring at room temperature for an hour. Then, 10.7 ml of 2-mercaptoethanol was added to the mixture followed by stirring for an additional 4 hours. After 100 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from toluene to give 37.6 g of the objective compound as white crystals.

Melting point: 128.degree.-130.degree. C.

    ______________________________________
    Elemental analysis: as C.sub.18 H.sub.18 O.sub.4 S
                    C    H
    ______________________________________
    Found (%)         65.26  5.55
    Calcd. (%)        65.43  5.49
    ______________________________________

NMR (CDCl.sub.3, .delta., ppm): 2.66(dt, J=2.1, 6.0 Hz, 2H), 3.69 (t, J=5.9 Hz, 2H), 3.89(s, 3H), 4.91 and 6.43(ABq, J=12.7 Hz, 2H), 5.09(s, 1H), 6.82-7.98(m, 7H)

IR (KBr tablet, cm.sup.-1) 3420, 1708, 1683, 1610, 1437, 1318, 1008

REFERENCE EXAMPLE 9

Methyl 11-(2-chloroethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound i):

Compound h, 20.0 g, obtained in Reference Example 8 was dissolved in 200 ml of dimethylformamide and, 12 ml of 2,4,6-cholidine and 4.0 g of lithium chloride were added to the solution. Under ice cooling, 5.4 ml of methanesulfonyl chloride was dropwise added to the mixture. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed successively with 1 N hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) and crystallized from hexane to give 20.8 g of the objective compound.

Melting point: 100.degree.-102.degree. C.

    ______________________________________
    Elemental analysis: as C.sub.18 H.sub.17 ClO.sub.3 S
                    C    H
    ______________________________________
    Found (%)         61.77  4.80
    Calcd. (%)        61.97  4.91
    ______________________________________

NMR (CDCl.sub.3, .delta., ppm): 2.54-3.62(m, 4H), 3.84(s, 3H), 5.04(s, 1H), 4.87 and 6.37(ABq, J=13.2 Hz, 2H), 6.76-8.12(m, 7H)

IR (CHCl.sub.3, cm.sup.-1): 1714, 1611, 1322, 1295, 1132, 1008

REFERENCE EXAMPLE 10

Methyl 11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound j):

Compound i, 10.1 g, obtained in Reference Example 9 was dissolved in 150 ml of acetonitrile and, 14.6 g of sodium iodide was added to the solution. The mixture was heated under reflux for 5 hours. After allowing it to stand for cooling, the reaction mixture was extracted with ethyl acetate and the extract was washed twice with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate =10:1) and further solidified with hexane to give 3.1 g of the objective compound as white solid.

Melting point: 111.degree.-113.degree. C.

    ______________________________________
    Elemental analysis: as C.sub.18 H.sub.17 IO.sub.3 S
                    C    H
    ______________________________________
    Found (%)         49.08  3.71
    Calcd. (%)        49.10  3.89
    ______________________________________

NMR (CDCl.sub.3, .delta., ppm): 2.68-3.22(m, 4H), 3.88(s, 3H), 5.09(s, 1H), 4.91 and 6.37(ABq, J=13.2 Hz, 2H), 6.78-8.08(m, 7H)

IR (CHCl.sub.3, cm.sup.-1): 1714, 1611, 1295, 1120, 1008

REFERENCE EXAMPLE 11

Methyl [2-(1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound k):

Compound j, 7.0 g, obtained in Reference Example 10 and 6.8 g of piperazine were heated under reflux for 8 hours in 300 ml of ethanol. The solvent was distilled off under reduced pressure. 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 3 followed by washing with diethyl ether. Next, 10 N sodium hydroxide aqueous solution was added to adjust pH to 13. Extraction was performed with 500 ml of ethyl acetate. After washing successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5.9 g of the objective compound as light yellow oil. The product was provided for the following reaction without further purification.

NMR (CDCl.sub.3, .delta., ppm): 2.19-3.33(m, 12H), 3.84(s, 3H), 5.06(s, 1H), 4.86 and 6.44(ABq, J=12.7 Hz, 2H), 6.76-8.12(m, 7H)

MS (m/Z): 402 (M.sup.+)

REFERENCE EXAMPLE 12

Methyl 2-methyl-2-[11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin]-2-yl]pr opionate (Compound l):

The objective compound was obtained as colorless oil in a manner similar to Reference Example 8 using Compound g obtained in Reference Example 7.

NMR (CDCl.sub.3, .delta., ppm): 1.56(s, 6H), 2.64(dt, J=2.2, 6.0 Hz, 2H), 3.65(s, 3H), 4.85 and 6.27(ABq, J=13.1Hz, 2H), 5.01(s, 1H), 6.7-7.4(m, 7H)

REFERENCE EXAMPLE 13

Methyl 2-methyl-2-[[11-(2-chloroethyl)thio-6,11-dihydrodibenz[b,e]oxepin]-2-yl]pr opionate (Compound m):

The objective compound was obtained as colorless oil in a manner similar to Reference Example 9 using Compound l obtained in Reference Example 12.

NMR (CDCl.sub.3, .delta., ppm): 1.57(s, 6H), 2.6-2.9(m, 2H), 3.2-3.4(m, 2H), 3.65(s, 3H), 4.85 and 6.23(ABq, J=13.1Hz, 2H), 5.04(s, 1H), 6.7-7.4(m, 7H)

REFERENCE EXAMPLE 14

Methyl 2-methyl-2-[[11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin]-2-yl]prop ionate (Compound n):

The objective compound was obtained as colorless oil in a manner similar to Reference Example 10 using Compound m obtained in Reference Example 13.

NMR (CDCl.sub.3, .delta., ppm): 1.56(s, 6H), 3.64(s, 3H), 5.27 (s, 1H)

REFERENCE EXAMPLE 15

Methyl 5-(2-hydroxyethyl)thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxyl ate (Compound o):

In 15.3 ml of methylene chloride was suspended 0.51 g of methyl 5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate. Under ice cooling, 0.27 ml of trifluoroacetic anhydride was added to the suspension followed by stirring at room temperature for an hour. Then, 0.14 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further an hour. After 10 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene to give 0.51 g of the objective compound as light yellow crystals.

Melting point: 107.degree.-109.degree. C.

NMR (CDCl.sub.3, .delta., ppm): 2.51-2.65(m, 3H), 2.75-3.03(m, 2H), 3.56-3.98(m, 4H), 3.87(s, 3H), 5.16(s, 1H), 7.14-7.25(m, 5H), 7.82(dd, J=1.5, 7.9 Hz, 1H), 7.91(s, 1H)

REFERENCE EXAMPLE 16

Methyl 5-(2-iodoethyl)thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound p):

Compound o, 0.46 g, obtained in Reference Example 15 and 1.10 g of triphenyl phosphine were suspended in 9.2 ml of benzene. While stirring under ice cooling, 0.65 ml of diethyl azodicarboxylate was added to the suspension followed by stirring at room temperature for 10 minutes. Then, 0.26 ml of iodomethane was added to the mixture followed by stirring at room temperature for 30 minutes. After 10 ml of ethyl acetate and 10 ml of water were added thereto, the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 0.57 g of the objective compound as pale yellow oil.

NMR (CDCl.sub.3, .delta., ppm): 2.70-3.08(m, 6H), 3.63-3.81(m, 2H), 3.89(s, 3H), 5.17(s, 1H), 7.17-7.32(m, 5H), 7.84(dd, J=1.7, 7.8 Hz, 1H), 7.92(s, 1H)

REFERENCE EXAMPLE 17

Methyl 5-(2-hydroxyethyl)thio-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound q):

The corresponding starting material was used, treated in a manner similar to Reference Example 15 and recrystallized from toluene to give the objective compound as pale yellow crystals.

Melting point: 130.degree.-132.degree. C.

NMR (CDCl.sub.3, .delta., ppm): 2.30-2.50(m, 3H), 3.51(t, J=15 6.2 Hz, 2H), 3.89(s, 3H), 5.31(s, 1H), 7.00(s, 1H), 7.02(s, 1H), 7.09-7.41(m, 5H), 7.91(dd, J=1.5, 7.9 Hz, 1H), 8.01(s, 1H)

REFERENCE EXAMPLE 18

Methyl 5-(2-iodoethyl)thio-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound r):

Compound q obtained in Reference Example 17 was used and treated in a manner similar to Reference Example 16 to give the objective compound as pale yellow oil.

NMR (CDCl.sub.3, .delta., ppm): 2.57-3.07(m, 4H), 3.92(s, 3H), 5.31(s, 1H), 7.01(s, 1H), 7.02(s, 1H), 7.09-7.41 (m, 5H), 7.91(dd, J=1.5, 7.9 Hz, 1H), 8.01(s, 1H)

REFERENCE EXAMPLE 19

Methyl (E)-11-[2-(1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-acetat e (Compound s):

The objective compound was obtained as colorless oil from Compound c (E-form) obtained in Reference Example 3 in a manner similar to Reference Example 11.

NMR (CDCl.sub.3, .delta., ppm): 1.95-3.0(m, 7H), 3.10(d, J=7.0 Hz, 2H), 3.83(s, 3H), 4.75-5.5(m, 2H), 6.20(t, J=7.0 Hz, 1H), 6.71(d, J=8.5 Hz, 1H), 6.95-7.45(m, 4H), 7.73(dd, J=2.2, 8.5 Hz, 1H), 7.99(d, J=2.2 Hz, 1H)

REFERENCE EXAMPLE 20

Methyl (E,Z)-11-[3-(methylsulfonyl)oxy]propylidine-6,11-dihydrodibenz[b,e]oxepin- 2-carboxylate (Comopund t):

[3-[(Tetrahydro-2H-pyran-2-yl)oxy]propyl]triphenylphosphonium bromide, 40.0 g, was suspended in 250 ml of tetrahydrofuran. Under ice cooling in nitrogen atmosphere, 50 ml of n-butyl lithium/hexane solution (1.6 N) was dropwise added to the suspension. After stirring at room temperature for an hour, 15.0 g of Compound a obtained in Reference Example 1 was added thereto followed by strirring at room temperature for 12 hours. After 50 ml of water was added to the reaction mixture, the mixture was extracted with 1 l of ethyl acetate. After washing thrice with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 500 ml of dioxane and 200 ml of water and 1.0 g of p-toluenesulfonic acid were added to the solution followed by heating under reflux for an hour. The mixture was concentrated under reduced pressure and the obtained residue was extracted with 1 l of ethyl acetate. After washing successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, the extract was dried over anhyrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; toluene:ethyl acetate =1.1) to give 9.8 g of methyl (E,Z)-11-(3-hydroxy)propylidene-6,11-dihydrodibenz[b,e]oxepin-2-car boxylate. A ratio of E/Z was approximately 3:7 by NMR.

The obtained product, 4.8 g, mainly composed of the Z-form and 10.0 g of p-toluenesulfonic acid were stirred in 250 ml of acetic acid at 100.degree. C. for 42 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 200 ml of methanol was added to the residue followed by heating under reflux for 3 hours. The solvent was distilled off under reduced pressure and the residue was extracted with 500 ml of ethyl acetate. After washing with saturated sodium bicarbonate aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to give 4.5 g of the product showing an E/Z ratio of about 1:1.

NMR (CDCl.sub.3, .delta., ppm): 2.17-2.72(m, 2H), 3.37-3.76(m, 2H), 3.77(s, 3H), 4.68-5.43(m, 1H), 5.70(t, J=7.4 Hz, 1.5H; Z form), 6.40(t, J=6.9 Hz, 1.5H; E form), 6.52-8.12(m, 7H)

The aforesaid product, 3.5 g, showing an E/Z ratio of about 1:1 was dissolved in 50 ml of pyridine and 1.7 ml of methanesulfonyl chloride was dropwise added under ice cooling. After stirring for an hour under ice cooling, the solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with 1N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 4.3 g of the objective compound as colorless oil.

NMR (CDCl.sub.3, .delta., ppm): --SO.sub.2 CH.sub.3 ; 2.93(s, 1.5H; E form), 3.00(s, 1.5H; Z form)

This product was provided for use in the following reaction step without particular purification. A ratio of E/Z was about 1:1.

REFERENCE EXAMPLE 21

Methyl 11-[2-(1-homopiperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carbox ylate (Compound u):

The objective compound was obtained as colorless oil in a manner similar to Reference Example 11, using Compound j obtained in Reference Example 10 and homopiperazine.

NMR (CDCl.sub.3, .delta., ppm): 1.4-2.0(m, 2H), 2.4-3.1(m, 12H), 3.85(s, 3H), 5.02(s, 1H), 4.87 and 6.44(ABq, J=12.9 Hz, 2H), 6.75-8.05(m, 7H)

IR (neat, cm.sup.-1): 2928, 1716, 1610, 1249, 1118, 1007

EXAMPLE 1

Methyl 11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11dihydrodibenz[b,e]oxepin-2-ca rboxylate (Compound la):

After 6.1 g of Compound j obtained in Reference Example 10 and 6.0 ml of 1-phenylpiperazine were heated under reflux in 300 ml of ethanol for 7.5 hours, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate: triethylamine=30:10:3). The resulting crude product was solidified with diethyl ether to give 3.1 g of the objective compound.

EXAMPLE 2

Methyl 11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate dihydrochloride (Compound 1a'):

Compound la, 1.2 g, obtained in Example 1 was dissolved in 200 ml of isopropanol and 2 ml of 6 N hydrochloric acid/isopropanol solution was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropanol to give 0.9 g of the objective compound.

In Examples 3 through 7 below, the objective compound was prepared using Compound j obtained in Reference Example 10 and the corresponding piperazine compound in a manner similar to Example 1.

EXAMPLE 3

Methyl 11-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 8a)

EXAMPLE 4

Methyl 11-[2-[4-(2-methoxyphenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 9a)

EXAMPLE 5

Methyl 11-[2-(4-benzyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 11a)

EXAMPLE 6

Methyl 11-[2-4-piperonyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2 -carboxylate (Compound 15a)

EXAMPLE 7

Methyl 11-[2-[4-(diphenylmethyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 16a)

In Examples 8 through 14 below, the objective compound was prepared using Compound j obtained in Reference Example 10 and the corresponding piperidine compound in a manner similar to Example 1.

EXAMPLE 8

Methyl 11-[2-(4-phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 37a)

EXAMPLE 9

Methyl 11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 38a)

EXAMPLE 10

Methyl 11-[2-[4-[2(3H)-benzimidazolon-1-yl]piperidino]ethyl]thio-6,11-dihydrodibe nz[b,e]oxepin-2-carboxylate (Compound 47a)

EXAMPLE 11

Methyl 11-[2-(4-phenyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 50a)

EXAMPLE 12

Methyl 11-[2-(4-benzyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 51a)

EXAMPLE 13

Methyl 11-[2-[ 4-(4-chlorobenzoyl)-1-piperidinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin -2-carboxylate (Compound 53a)

EXAMPLE 14

Methyl 11-[2-(1-phenyl-1,3,8-triazaspiro[4.5]decan-4-on-8-yl)ethyl]thio-6,11-dihy drodibenz[b,e]oxepin-2-carboxylate (Compound 58a)

In Examples 15 through 17 below, the objective compound was prepared using the corresponding starting material n, p or r and 4-benzylpiperidine in a manner similar to Example 1.

EXAMPLE 15

Methyl 2-methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b, e]oxepin-2-yl]propionate (Compound 41a)

EXAMPLE 16

Methyl 5-[2-(4-benzyl-1-piperidinyl)ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclo hepten-3-carboxylate (Compound 101a)

EXAMPLE 17

Methyl 5-[2-(4-benzyl-1-piperidinyl)ethyl]thio- 5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound 103a)

EXAMPLE 18

Methyl (E,Z)-11-[3-(4-benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz[b,e]ox epin-2-carboxylate (Compound E/Z-85a)

The objective compound was prepared using Compound t obtained in Reference Example 20 and 4-benzylpiperidine in a manner similar to Example 1. A ratio of E/Z was 1:1.

In Examples 19 through 22 below, the objective compound was prepared using the corresponding starting material c or e and the corresponding piperazine or piperidine compound in a manner similar to Example 1.

EXAMPLE 19

Methyl (E)-11-[2-[4-(4-fluorophenyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound E-73a)

EXAMPLE 20

Methyl (E,Z)-11-[2-[4-(2-pyrimidyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound E/Z-76a)

EXAMPLE 21

Methyl (E)-11-[2-(4-benzyl-1-piperidinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepi n-2-acetate (Compound E-96a)

EXAMPLE 22

Methyl (E)-11-[2-[4-[2(3H)-benzimidazolon-1-yl]piperidino]ethylidene]-6,11-dihydr odibenz[b,e]oxepin-2-acetate (Compound E-98a)

Physicochemical properties of compounds obtained in Examples 1 through 22 are shown in Table 7-1. In Tables 7-1 to 7-5, symbol * in solvent for recrystallization means solidification by tritylation.

                                      TABLE 7-1
    __________________________________________________________________________
                 MP (.degree.C.)
    Example      [Solvent
    No.          for re-                               Elemental analysis
                                                       (%)
    (Compound
          Appear-
                 crystal-
                      NMR               IR      MS     Upper column: found
    No.)  ance   lization]
                      (solvent) .delta., ppm
                                        (method) cm.sup.-1
                                                m/z    Lower column:
    __________________________________________________________________________
                                                       calcd.
     1    white  129-130
                      (CDCl.sub.3)2.30-3.34(m, 12H), 3.82
                                        (KBr tablet)
                                                474(M+)
                                                       C.sub.28 H.sub.30
                                                       N.sub.2 O.sub.3 S
     (1a) crystal
                 [isopro-
                      (s, 1H), 5.03(s, 1H), 4.83&6.39
                                        3450, 2948,    C   H   N
                 panol]
                      (ABq, J=13.1Hz, 2H), 6.30-8.06
                                        2826, 1711,    71.11
                                                           6.23
                                                               5.80
                      (m, 12H)          1610, 1598,    70.86
                                                           6.37
                                                               5.90
                                        1242
     2    white  188   --               (KBr tablet)
                                                --     C.sub.28 H.sub.32
                                                       Cl.sub.2 N.sub.2
                                                       O.sub.3 S
     (1a')
          crystal
                 (dec.)                 1714, 1599,    C   H   N
                 [isopro-               1494, 1118,    61.75
                                                           6.21
                                                               5.15
                 panol]                 1006           61.42
                                                           5.89
                                                               5.12
     3    yellow --   (CDCl.sub.3)2.4-3.3(m, 12H), 3.81
                                        (CHCl.sub.3)
                                                492(M+)
                                                        --
     (8a) amorphous   (s, 3H), 3.83(s, 3H), 4.86&6.41
                                        2824, 1713,
                      (ABq, J=11.7Hz, 2H), 5.03(s, 1H),
                                        1611, 1508,
                      6.7-7.4(m, 8H), 7.67(dd, J=2.5,
                                        1294, 1132,
                      8.5Hz, 1H), 7.88(d, J=2.5Hz, 1H)
                                        1120, 1005
     4    colorless
                 --   (CDCl.sub.3)2.4-3.3(m, 12H), 3.81
                                        (CHCl.sub.3)
                                                504(M+)
                                                        --
     (9a) oil         (s, 3H), 3.83(s, 3H), 4.85&6.44
                                        2936, 2806,
                      (ABq, J=12.8Hz, 2H), 5.07(s, 1H),
                                        1708, 1610,
                      6.7-7.4(m, 9H), 7.76(dd, J=2.3,
                                        1496, 1005
                      8.5Hz, 1H), 7.98(d, J=2.3Hz, 1H)
     5    colorless
                 --   (CDCl.sub.3)2.05-2.65(m, 12H), 3.46
                                        (CHCl.sub.3)
                                                487(M+)
                                                        --
    (11a) oil         (s, 2H), 3.83(s, 3H), 4.86&6.45
                                        2816, 1714,
                      (ABq, J=12.0Hz, 2H), 5.06(s, 1H),
                                        1611, 1120,
                      6.98-7.44(m, 9H), 7.78(dd, J=2.2,
                                        1006
                      8.6Hz, 1H), 7.98(d, J=2.2Hz, 1H)
     6    colorless
                 --   (CDCl.sub.3)2.25-2.75(m, 12H), 3.36
                                        (CHCl.sub.3)
                                                532(M+)
                                                        --
    (15a) oil         (s, 2H), 3.81(s, 3H), 4.82&6.40
                                        1702, 1602,
                      (ABq, J=12.2Hz, 2H), 5.03(s, 1H),
                                        1296, 1121,
                      5.85(s, 2H), 6.55-6.8(m, 3H),
                                        1004
                      6.82(d, J=4.6Hz, 1H), 7.1-7.35
                      (m, 4H), 7.72(dd, J=2.5, 8.5Hz,
                      1H), 7.93(d, J=2.5Hz, 1H)
     7    colorless
                 --   (CDCl.sub.3)3.84(s, 3H), 4.20(s,
                                        (CHCl.sub.3)
                                                564(M+)
                                                        --
    (16a) oil         1H), 4.87&6.43(ABq, J=12.7Hz,
                                        1715, 1610,
                      2H), 5.07(s, 1H), 6.84(d, J=8.6
                                        1495, 1241,
                      Hz, 1H), 7.78(dd, J=2.2, 8.6Hz,
                                        1117, 1005
                      1H), 7.97(d, J=2.2Hz, 1H)
     8    colorless
                 --   (CDCl.sub.3)1.5-3.2(m, 13H), 3.84
                                        (CHCl.sub.3)
                                                473(M+)
                                                        --
    (37a) oil         (s, 3H), 4.95&6.50(ABq, J=12.7
                                        1719, 1609,
                      Hz, 2H), 5.14(s, 1H), 6.87(d,
                                        1496, 1247,
                      J=8.5Hz, 1H), 7.05-7.45(m, 9H),
                                        1128, 1009
                      7.81(dd, J=2.2, 8.5Hz, 1H), 8.03
                      (d, J=2.2Hz, 1H)
     9    colorless
                 --   (CDCl.sub.3)1.0-2.2(m, 7H), 2.2-3.2
                                        (CHCl.sub.3)
                                                487(M+)
                                                        --
    (38a) oil         (m, 8H), 3.83(s, 3H), 4.85&6.41
                                        2924, 1713,
                      (ABq, J=13.9Hz, 2H), 5.06(s, 1H),
                                        1611, 1295,
                      6.8-7.4(m, 10H), 7.75(dd, J=2.0,
                                        1120, 1007
                      8.5Hz, 1H), 7.95(d, J=2.0Hz, 1H)
    10    colorless
                 --   (DMSO-d.sub.6)1.5-3.0(m, 12H), 3.82
                                        (CHCl.sub.3)
                                                529(M+)
                                                        --
    (47a) oil         (s, 3H), 4.12(m, 1H), 5.08&6.31
                                        1718, 1686,
                      (ABq, J=12.7Hz, 2H), 5.51(s, 1H),
                                        1251, 1119,
                      6.91(d, J=8.6Hz, 1H), 6.95-7.5
                                        1015
                      (m, 8H), 7.75(dd, J=2.2, 8.6Hz,
                      1H), 8.04(d, J=2.2Hz, 1H)
    11    colorless
                 --   (CDCl.sub.3)3.87(s, 3H), 4.90&6.45
                                        (CHCl.sub.3)
                                                489(M+)
                                                        --
    (50a) oil         (ABq, J=12.9Hz, 2H), 5.09(s, 1H),
                                        1715, 1610,
                      6.86(d, J=8.6Hz, 1H), 7.79(dd,
                                        1247, 1117,
                      J=2.2, 8.6Hz, 1H), 8.00(d, J=
                                        1005
                      2.2Hz, 1H)
    12    colorless
                 --   (CDCl.sub.3)1.2-2.7(m, 12H), 2.73
                                        (neat)  503(M+)
                                                        --
    (51a) oil         (s, 2H), 3.86(s, 3H), 4.88&6.44
                                        2916, 1696,
                      (ABq, J=12.7Hz, 2H), 5.06(s, 1H),
                                        1609, 1570,
                      6.84(d, J=8.6Hz, 1H), 7.00-7.40
                                        1491, 1113,
                      (m, 9H), 7.78(dd, J=2.2, 8.6Hz,
                                        1008
                      1H), 7.98(d, J=2.2Hz, 1H)
    13    colorless
                 --   (CDCl.sub.3)1.80-3.50(m, 13H), 3.87
                                        (CHCl.sub.3)
                                                536(M+)
                                                        --
    (53a) oil         (s, 3H), 4.90&6.43(ABq, J=12.7
                                        2954, 2930,
                      Hz, 2H), 5.09(s, 1H), 6.86(d, J=
                                        1715, 1293,
                      8.6Hz, 1H), 7.20-7.35(m, 4H),
                                        1132, 1121
                      7.43(d, J=8.6Hz, 2H), 7.85(d,
                      J=8.6Hz, 2H), 7.70-7.95(m, 2H)
    14    colorless
                 --   (CDCl.sub.3)1.6-1.8(m, 2H), 2.4-3.0
                                        (CHCl.sub.3)
                                                543(M+)
                                                        --
    (58a) oil         (m, 10H), 3.86(s, 3H), 4.72(s,
                                        2926, 1703,
                      2H), 4.90&6.46(ABq, J=12.8Hz,
                                        1600, 1499,
                      2H), 5.13(s, 1H), 6.6-7.4(m,
                                        1376, 1243,
                      10H), 7.75(dd, J=2.0, 8.5H, 1H),
                                        1118, 1006
                      8.00(d, J=2.0Hz, 1H)
    15    colorless
                 --   (CDCl.sub.3)1.1-2.9(m, 15H), 1.55(s,
                                        (CHCl.sub.3)
                                                529(M+)
                                                        --
    (41a) oil         6H), 3.61(s, 3H), 4.99(s, 1H),
                                        2922, 1726,
                      4.80&6.29(ABq, J=13.0Hz, 2H),
                                        1496, 1265,
                      6.7-7.35(m, 12H)  1147, 1124,
                                        1105, 1013,
                                        906
    16    pale   --   (CDCl.sub.3)1.13-1.99(m, 9H), 2.35
                                        (CHCl.sub.3)
                                                485(M+)
                                                        --
    (101a)
          yellow      -2.99(m, 8H), 3.62-3.96(m, 2H),
                                        1717, 1301,
          oil         3.83(s, 3H), 5.16(s, 1H), 6.95
                                        1280, 1105
                      -7.30(m, 10H), 7.80(dd, J=1.5,
                      7.9Hz, 1H), 7.92(s, 1H)
    17    pale   --   (CHCl.sub.3)1.11-2.03(m, 9H), 2.35
                                        (CHCl.sub.3)
                                                483(M+)
                                                        --
    (103a)
          yellow      (s, 2H), 2.38-2.81(m, 4H), 3.90
                                        1716, 1299,
          oil         (s, 3H), 5.29(s, 1H), 7.01(s,
                                        1279, 1110
                      1H), 7.02(s, 1H), 7.06-7.42(m,
                      10H), 7.92(dd, J=1.1, 9.7Hz, 1H),
                      7.99(s, 1H)
    18    colorless
                 --   (CDCl.sub.3)0.8-2.0(m, 7H), 2.1-2.9
                                        (neat)  467(M+)
                                                        --
    (E/Z-85a)
          oil         (m, 8H), 3.78(s, 3H), 5.18(bs,
                                        2916, 1718,
                      2H), 5.65(t, J=7.0Hz; Z form),
                                        1604, 1118,
                      5.99(t, J=7.0Hz; E form), 6.6-
                                        1004
                      8.0(m, 12H), 7.93(d, J=2.4Hz, 1H)
    19    colorless
                 --   (CDCl.sub.3)2.3-3.4(m, 10H), 3.83
                                        (KBr tablet)
                                                458(M+)
                                                        --
    (E-73a)
          amorphous   (s, 3H), 4.7-5.6(m, 2H), 6.25(t,
                                        1707, 1605,
                      J=5.5Hz, 1H), 6.6-7.5(m, 9H),
                                        1504, 1240,
                      7.73(dd, J=2.2, 8.6Hz, 1H), 8.00
                                        1002
                      (d, J=2.2Hz, 1H)
    20    colorless
                 --   (CDCl.sub.3)2.35-2.7(m, 4H), 3.0-
                                        (KBr tablet)
                                                442(M+)
                                                        --
    (E/Z-76a)
          oil         3.35(m, 2H), 3.88(s, 3H), 3.65-
                                        1713, 1585,
                      4.0(m, 4H), 4.6-5.6(m, 2H), 6.30
                                        1357, 1244,
                      (t, J=6.8Hz; Z form), 6.45(t, J=
                                        1002
                      4.8Hz; E form), 6.79(d, J=8.6Hz,
                      1H), 7.0-7.5(m, 5H), 7.78(dd, J=



                      2.2, 8.6Hz, 1H), 8.05(d, J=2.2Hz,
                      1H), 8.27(d, J=4.6Hz, 2H)
    21    colorless
                 --   (CDCl.sub.3)1.0-3.2(m, 11H), 3.47
                                        (neat)  467(M+)
                                                        --
    (E-96a)
          oil         (s, 2H), 3.61(s, 3H), 4.85-5.3
                                        2918, 1735,
                      (m, 2H), 6.14(t, J=6.8Hz, 1H),
                                        1489, 1011
                      6.66(d, J=9Hz, 1H), 6.8- 7.34(m,
                      11H)
    22    colorless
                 --   (CDCl.sub.3)1.35-3.35(m, 11H), 3.54
                                        (CHCl.sub.3)
                                                509(M+)
                                                        --
    (E-98a)
          oil         (s, 2H), 3.68(s, 3H), 4.65-5.5
                                        1689, 1486,
                      (m, 2H), 6.22(t, J=6.6Hz, 1H),
                                        1148, 1008
                      6.73(d, J=8.4Hz, 1H), 6.8-7.5
                      (m, 10H)
    __________________________________________________________________________

EXAMPLE 23

11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ca rboxylic acid.monohydrate (Compound 1b'):

Compound 1a, 0.8 g, obtained in Example 1 was dissolved in a solvent mixture of 300 ml of methanol and 10 ml of water and, 80 mg of sodium hydroxide was added to the solution followed by heating under reflux for 4 hours. After allowing to cool, 4 N hydrochloric acid aqueous solution was added to the mixture to adjust pH to 7. The mixture was concentrated under reduced pressure. Precipitated crystals were taken by filtration. After washing with water, 0.7 g of the objective compound was obtained as white solid.

In Examples 24 through 30 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.

EXAMPLE 24

11-[2-[4-(4-Fluorophenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e}ox epin-2-carboxylic acid (Compound 8b)

EXAMPLE 25

11-[2-[4-(2-Methoxyphenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid (Compound 9b)

EXAMPLE 26

11-[2-(4-Benzyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ca rboxylic acid.monohydrate (Compound 11b')

EXAMPLE 27

11-[2-(4-Piperonyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2 -carboxylic acid (Compound 15b)

EXAMPLE 28

11-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid (Compound 16b)

EXAMPLE 29

11-[2-(4-Phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ca rboxylic acid.0.5 hydrate (Compound 37b')

EXAMPLE 30

11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-ca rboxylic acid (Compound 38b)

EXAMPLE 31

Sodium 11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 38b')

Compound 38b, 45 g, obtained in Example 30 was suspended in 500 ml of methanol and 5.3 g of sodium methoxide was added to the suspension followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure. The resulting crude product was solidified with hexane to give 47 g of the objective compound.

EXAMPLE 32

11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]ethyl]thio-6,11-dihydrodiben z[b,e]oxepin-2-carboxylic acid.0.5 isopropanol.0.5 hydrate (Compound 47b'):

The objective compound was prepared by hydrolyzing Compound 47a obtained in Example 10 in a manner similar to Example 23.

EXAMPLE 33

Sodium 11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]ethyl]thio-6,11-dihydrodibe nz[b,e]oxepin-2-carboxylate.2.5 hydrate (Compound 47b")

Compound 47b' obtained in Example 32 was converted into the sodium salt in a manner similar to Example 31.

In Examples 34 through 38 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.

EXAMPLE 34

11-[2-(4-Phenyl-4-hydroxy-1- piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid.0.75 hydrate (Compound 50b')

EXAMPLE 35

11-[2-(4-Benzyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid.0.2 isopropanol (Compound 51b')

EXAMPLE 36

11-[2-[4-(4-Chlorobenzoyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid.0.1 isopropanol. 0.5 hydrate (Compound 53b')

EXAMPLE 37

11-[2-(1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-on-8-yl)ethyl]thio-6,11-dihyd rodibenz[b,e]oxepin-2-carboxylic acid. 0.25 hydrate (Compound 58b')

EXAMPLE 38

2-Methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[ b,e]oxepin-2-yl]propionate (Compound 41)

EXAMPLE 39

5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cycloh epten-3-carboxylic acid.0.5 fumarate (Compound 101b'):

Compound 101a, 0.33 g, obtained in Example 16 was hydrolyzed in a manner similar to Example 23 to give 0.3 g of the corresponding Compound 101b. This compound was dissolved in 50 ml of acetone and 80 mg of fumaric acid was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from isopropanol to prepare 0.14 g of the objective compound.

EXAMPLE 40

5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5H-dibenzo[a,d]cyclohepten-3-carbox ylic acid.0.5 fumarate.0.5 isopropanol (Compound 103b'):

The objective compound was prepared using Compound 103a obtained in Example 17 in a manner similar to Example 39.

EXAMPLE 41

(E,Z)-11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz[b,e]oxe pin-2-carboxylic acid.1.5 hydrate (Compound 85b'):

The objective compound was prepared by hydrolyzing Compound E/Z-85a obtained in Example 18 in a manner similar to Example 23.

A ratio of E/Z was 38:62.

In Examples 42 and 43 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.

EXAMPLE 42

(E)-11-[2-[4-(4-Fluorophenyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylic acid.isopropanol. monohydrate (Compound E-73b')

EXAMPLE 43

(E,Z)-11-[2-[4-(2-Pyrimidyl)-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b ,e]oxepin-2-carboxylic acid (Compound E/Z-76b)

A ratio of E/Z was 85:15.

EXAMPLE 44

(E)-11-[2-(4-Benzyl-1-piperidinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin -2-acetic acid.0.5 fumarate (Compound E-96b'):

Compound E-96a, 2.0 g, obtained in Example 21 was hydrolyzed in a manner similar to Example 23 to give 1.7 g of the corresponding Compound E-96b. This compound was dissolved in 200 ml of acetone and 0.43 g of fumaric acid was added to the solution followed by stirring at room temperature for an hour. The precipitated crystals were taken by filtration to give 1.5 g of the objective compound.

EXAMPLE 45

(E)-11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]ethylidene]-6,11-dihydro dibenz[b,e]oxepin-2-acetic acid. monohydrate (Compound E-98b'):

The objective compound was prepared by hydrolyzing Compound E-98a obtained in Example 22 in a manner similar to Example 23.

EXAMPLE 46

Sodium (E)-11-[2-[4-[2(3H)-benzimidazolon-1-yl]piperidino]ethylidene]-6,11-dihydr odibenz[b,e]oxepin-2-acetate (Compound E-98b"):

Compound E-98b' obtained in Example 45 was converted into the sodium salt in a manner similar to Example 31.

Physicochemical properties of the compounds obtained in Examples 23 through 46 are shown in Table 7-2.

                                      TABLE 7-2
    __________________________________________________________________________
                MP (.degree.C.)
    Example     [Solvent
    No.         for re-                               Elemental analysis (%)
    (Compound
          Appear-
                crystal-
                       NMR              IR      MS    Upper column: found
    No.)  ance  lization]
                       (solvent) .delta., ppm
                                        (method) cm.sup.-1
                                                m/z   Lower column:
    __________________________________________________________________________
                                                      calcd.
    23    white 215    (DMSO-d.sub.6)2.50-3.83(m, 12H),
                                        (KBr tablet)
                                                460(M+)
                                                      C.sub.27 H.sub.28
                                                      N.sub.2 O.sub.3
                                                      S.H.sub.2 O
     (1b')
          crystal
                (dec.) 5.08&6.23(ABq, J=12.5Hz, 2H),
                                        3400, 2936,   C   H   N
                [isopro-
                       5.51(s, 1H), 6.79-8.04(m, 12H)
                                        2824, 1694,   67.39
                                                          6.06
                                                              5.59
                panol]                  1599, 1232    67.76
                                                          6.32
                                                              5.85
    24    white 165-166
                       (DMSO-d.sub.6)2.3-2.8(m, 8H), 3.0-
                                        (KBr tablet)
                                                478(M+)
                                                      C.sub.27 H.sub.27
                                                      FN.sub.2 O.sub.3 S
     (8b) amorphous
                (dec.)  3.1(m, 4H), 5.05&6.28(ABq, J=
                                        3400, 1607,   C   H   N
                [isopro-
                       12.6Hz, 2H), 5.45(s, 1H), 6.85-
                                        1509, 1384,   67.55
                                                          5.65
                                                              5.58
                panol]*
                       7.1(m, 5H), 7.4-7.5(m, 4H), 7.71
                                        1232          67.76
                                                          5.69
                                                              5.85
                       (dd, J=2.2, 8.7Hz, 1H), 7.99(d,
                       J=2.2Hz, 1H)
    25    white 171-175
                       (DMSO-d.sub.6)3.0-3.7(m, 12H), 3.81
                                        (KBr tablet)
                                                490(M+)
                                                      C.sub.28 H.sub.30
                                                      N.sub.2 O.sub.4 S
     (9b) amorphous
                [isopro-
                       (s, 3H), 5.10&6.16(ABq, J=12.9
                                        1694, 1609,   C   H   N
                panol]*
                       Hz, 2H), 5.54(s, 1H), 6.90(d,
                                        1499, 1455,   68.23
                                                          6.35
                                                              5.88
                       J=8.5Hz, 1H), 6.9-7.1(m, 4H),
                                        1200, 1115,   68.55
                                                          6.16
                                                              5.71
                       7.4-7.65(m, 4H), 7.74(dd, J=2.2,
                                        1013
                       8.5Hz, 1H), 8.06(d, J=2.2Hz, 1H)
    26    white 112-115
                       (DMSO-d.sub.6)2.2-2.7(m, 12H), 3.42
                                        (KBr tablet)
                                                474(M+)
                                                      C.sub.28 H.sub.30
                                                      N.sub.2 O.sub.3
                                                      S.H.sub.2 O
    (11b')
          crystal
                (dec.) (s, 2H), 5.01&6.24(ABq, J=12.7
                                        3400, 1609,   C   H   N
                [iso-  Hz, 2H), 5.39(s, 1H), 6.81(d, J=
                                        1384, 1232,   68.33
                                                          6.25
                                                              5.54
                propyl 8.6Hz, 1H), 7.2-7.5(m, 9H), 7.69
                                        1008          68.27
                                                          6.55
                                                              5.69
                ether] (dd, J=2.2, 8.6Hz, 1H), 7.95(d,
                       2.2Hz, 1H)
    27    white 218-220
                       (DMSO-d.sub.6)2.2-2.7(m, 12H), 3.34
                                        (KBr tablet)
                                                518(M+)
                                                      C.sub.29 H.sub.30
                                                      N.sub.2 O.sub.5 S
    (15b) crystal
                (dec.) (s, 2H), 5.04&6.26(ABq, J=12.7
                                        1670, 1609,   C   H   N
                [isopro-
                       Hz, 2H), 5.43(s, 1H), 5.98(s,
                                        1491, 1242,   67.09
                                                          5.95
                                                              5.24
                panol] 2H), 6.72(d, J=7.9Hz, 1H), 6.8-
                                        1040          67.16
                                                          5.83
                                                              5.40
                       6.85(m, 2H), 6.86(d, J=8.6Hz,
                       1H), 7.35-7.5(m, 4H), 7.71(dd,
                       J=2.2, 8.6Hz, 1H), 7.98(d, J=
                       2.2Hz, 1H)
    28    white 145-148
                       (DMSO-d.sub.6)2.2-2.7(m, 12H), 4.26
                                        (KBr tablet)
                                                550(M+)
                                                      C.sub.34 H.sub.34
                                                      N.sub.2 O.sub.3 S
    (16b) crystal
                [isopro-
                       (s, 1H), 5.04&6.23(ABq, J=12.6
                                        1683, 1608,   C   H   N
                panol] Hz, 2H), 5.44(s, 1H), 6.86(d,
                                        1493, 1451,   73.98
                                                          6.35
                                                              5.00
                       J=8.6Hz, 1H), 7.70(dd, J=2.2,
                                        1232, 1006    74.15
                                                          6.22
                                                              5.09
                       8.6Hz, 1H), 7.98(d, J=2.2Hz, 1H)
    29    white 182-184
                       (DMSO-d.sub.6)1.65-3.0(m, 13H), 5.06&
                                        (KBr tablet)
                                                459(M+)
                                                      C.sub.28 H.sub.29
                                                      NO.sub.3 S.0.5H.sub.2
                                                      O
    (37b')
          crystal
                [isopro-
                       6.27(ABq, J=12.7Hz, 2H), 5.48
                                        1680, 1605,   C   H   N
                panol] (s, 1H), 6.88(d, J=8.5Hz, 1H),
                                        1494, 1318,   71.85
                                                          6.23
                                                              2.98
                       7.15-7.5(m, 9H), 7.72(dd, J=2.2,
                                        1233, 1104,   71.77
                                                          6.45
                                                              2.99
                       8.5Hz, 1H), 8.01(d, J=2.2Hz, 1H)
                                        1007
    30    white 205-206
                       (DMSO-d.sub.6)1.0-1.9(m, 7H), 2.2-
                                        (KBr tablet)
                                                473(M+)
                                                      C.sub.29 H.sub.31
                                                      NO.sub.3 S
    (38b) crystal
                [isopro-
                       2.85(m, 8H), 5.03&6.25(ABq, J=
                                        2912, 1687,   C   H   N
                panol] 12.6Hz, 2H), 5.42(s, 1H), 6.86
                                        1608, 1494,   73.48
                                                          6.72
                                                              2.92
                       (d, J=8.6Hz, 1H), 7.1-7.5(m, 9H),
                                        1449, 1323,   73.54
                                                          6.60
                                                              2.96
                       7.70(dd, J=2.2, 8.6Hz, 1H), 7.97
                                        1229, 1019
                       (d, J=2.2Hz, 1H)
    31    white 119-121
                        --              (KBr tablet)
                                                --    C.sub.29 H.sub.30
                                                      NO.sub.3 SNa.0.5H.sub.2
                                                      O
    (38b')
          solid [hexane]*               2918, 1612,   C   H   N
                                        1582, 1548,   68.80
                                                          6.44
                                                              2.93
                                        1385, 1252,   69.03
                                                          6.19
                                                              2.78
                                        1227, 1105,
                                        1011
    32    white 185-188
                       (DMSO-d.sub.6)1.55-3.1(m, 12H),
                                        (KBr tablet)
                                                515(M+)
                                                      C.sub.29 H.sub.29
                                                      N.sub.3 O.sub.4
                                                      S.0.5C.sub.3 H.sub.8
                                                      O.
    (47b')
          crystal
                [aceto-
                       4.14(m, 1H), 5.07&6.28(ABq, J=
                                        1695, 1485,   0.5C.sub.2 H.sub.3 N
                nitrile/
                       12.7Hz, 2H), 5.48(s, 1H), 6.89
                                        1386          C   H   N
                isopro-
                       (d, J=8.6Hz, 1H), 6.95-7.5(m,  66.41
                                                          5.90
                                                              8.45
                panol] 8H), 7.72(dd, J=2.2, 8.6Hz, 1H),
                                                      66.75
                                                          6.22
                                                              8.57
                       8.06(d, J=2.2Hz, 1H), 10.83(s,
                       1H)
    33    white 224-227
                        --              (KBr tablet)
                                                --    C.sub.29 H.sub.28
                                                      N.sub.3 O.sub.4
                                                      SNa.2.5H.sub.2 O
     (47b")
          crystal
                [methanol]              1683, 1583,   C   H   N
                                        1543, 1485,   59.77
                                                          5.72
                                                              7.10
                                        1379, 1256,   59.78
                                                          5.71
                                                              7.21
                                        1229, 1109,
                                        1006
    34    white 150-154
                       (DMSO-d.sub.6)1.5-1.6(m, 2H), 1.8-
                                        (KBr tablet)
                                                475(M+)
                                                      C.sub.28 H.sub.29
                                                      NO.sub.4 S.0.75H.sub.2
                                                      O
    (50b')
          crystal
                [isopro-
                       2.0(m, 2H), 2.35-2.75(m, 8H),
                                        1611, 1584,   C   H   N
                panol] 5.05&6.28(ABq, J=12.7Hz, 2H),
                                        1550, 1375,   68.60
                                                          6.41
                                                              2.88
                       6.87(d, J=8.5Hz, 1H), 7.15-7.5
                                        1228, 1006    68.76



                                                          6.29
                                                              2.86
                       (m, 9H), 7.71(dd, J=2.1, 8.5Hz,
                       1H), 8.01(d, J=2.1Hz, 1H)
    35    white 232    (DMSO-d.sub.6)1.25-1.5(m, 4H), 2.2-
                                        (KBr tablet)
                                                489(M+)
                                                      C.sub.29 H.sub.31
                                                      NO.sub.4 S.0.2C.sub.3
                                                      H.sub.8 O
    (51b')
          crystal
                [isopro-
                       2.75(m, 8H), 2.63(s, 2H), 5.02&
                                        1608, 1492,   C   H   N
                panol] 6.25(ABq, J=12.6Hz, 2H), 5.41(s,
                                        1383, 1232,   70.98
                                                          6.43
                                                              2.49
                       1H), 6.85(d, J=8.6Hz, 1H), 7.15-
                                        1107, 1009    70.87
                                                          6.55
                                                              2.79
                       7.45(m, 9H), 7.70(dd, J=2.2, 8.6
                       Hz, 1H), 7.96(d, J=2.2Hz, 1H)
    36    pale  138-139
                       (DMSO-d.sub.6)1.4-3.5(m, 13H), 5.05&
                                        (KBr tablet)
                                                522(M+)
                                                      C.sub.29 H.sub.28
                                                      ClNO.sub.4 S.0.1
    (53b')
          yellow
                [iso-  6.27(ABq, J=12.6Hz, 2H), 5.46
                                        1676, 1608,   C.sub.6 H.sub.14
                                                      O.0.5H.sub.2 O
    solid       propyl (s, 1H), 6.87(d, J=8.6Hz, 1H),
                                        1587, 1376,   C   H   N
                ether]*
                       7.35-7.5(m, 4H), 7.59(d, J=8.6Hz,
                                        1229, 1091,   65.81
                                                          5.39
                                                              2.22
                       2H), 7.71(dd, J=2.1, 8.6Hz, 1H),
                                        1009          65.46
                                                          5.68
                                                              2.58
                       7.97(d, J=8.6Hz, 2H), 7.99(d,
                       J=2.1Hz, 1H)
    37    white 186-189
                       (DMSO-d.sub.6)1.56(d, J= 13.6Hz, 2H),
                                        (KBr tablet)
                                                529(M+)
                                                      C.sub.30 H.sub.31
                                                      N.sub.3 O.sub.4
                                                      S.0.25H.sub.2 O
    (58b')
          solid [isopro-
                       2.4-2.9(m, 10H), 4.57(s, 2H),
                                        1710, 1598,   C   H   N
                panol] 5.06&6.26(ABq, J=12.6Hz, 2H),
                                        1497, 1379,   67.29
                                                          5.82
                                                              7.69
                       5.54(s, 1H), 6.75-7.2(m, 5H),
                                        1105, 1009    67.46
                                                          5.94
                                                              7.87
                       6.88(d, J=8.5Hz, 1H), 7.72(dd,
                       J=2.1, 8.5Hz, 1H), 8.04(d, J=
                       2.1Hz, 1H), 8.64(s, 1H)
    38    white 84-86  (DMSO-d.sub.6)1.1-1.3(m, 2H), 1.35-
                                        (KBr tablet)
                                                515(M+)
                                                      C.sub.32 H.sub.37
                                                      NO.sub.3 S
    (41b) solid [water]*
                        1.6(m, 3H), 1.43&1.45(each s,
                                        2926, 1720,   C   H   N
                       6H), 1.85-2.0(m, 2H), 2.35-2.9
                                        1496, 1453,   74.21
                                                          7.45
                                                              2.66
                       (m, 8H), 5.33(s, 1H), 4.91&6.13
                                        1231, 1123,   74.53
                                                          7.23
                                                              2.72
                       (ABq, J=12.8Hz, 2H), 6.76(d, J=
                                        1014
                       8.4Hz, 1H), 7.1-7.45(m, 11H)
    39    pale  127-130
                        (CD.sub.3 OD)1.20-1.86(m, 5H), 2.35-
                                        (KBr tablet)
                                                469(M+)
                                                      C.sub.30 H.sub.31
                                                      NO.sub.2 S.0.5C.sub.4
                                                      H.sub.4 O.sub.4
    (101b')
          yellow
                [isopro-
                        3.20(m, 12H), 3.56-3.94(m, 2H),
                                        3420, 2920,   C   H   N
          crystal
                panol] 5.21(s, 1H), 7.03-7.33(m, 10H),
                                        1695, 1585,   72.60
                                                          6.60
                                                              2.55
                       7.75-7.86(m, 2H) 1453, 1372,   72.84
                                                          6.30
                                                              2.65
                                        1244
    40    pale  100-115
                       (DMSO-d.sub.6)1.18-2.11(m, 5H), 2.26-
                                        (KBr tablet)
                                                467(M+)
                                                      C.sub.30 H.sub.29
                                                      NO.sub.2 S.0.5C.sub.4
                                                      H.sub.4 O.sub.4.
    (103b')
          yellow
                (dec.) 2.60(m, 8H), 2.63-2.92(m, 2H),
                                        3400, 2922,   0.5C.sub.3 H.sub.8 O
    crystal     [isopro-
                       5.44(s, 1H), 6.99(s, 2H), 7.01-
                                        1698, 1582,   C   H   N
                panol] 7.49(m, 10H), 7.84(dd, J=1.3,
                                        1372          72.23
                                                          6.51
                                                              2.41
                       9.0Hz, 1H), 8.02(s, 1H)        72.41
                                                          6.35
                                                              2.52
    41    white 146-149
                       (DMSO-d.sub.6)5.70(t, J=6.7Hz; Z
                                        (KBr tablet)
                                                453(M+)
                                                      C.sub.30 H.sub.31
                                                      NO.sub.3.1.5H.sub.2 O
    (E/Z-85b')
          solid [water]*
                       form), 6.06(t, J=7.5Hz; E form),
                                        2920, 1605,   C   H   N
                       6.80(d, J=8.4Hz; E form), 6.88
                                        1486, 1454,   75.09
                                                          7.22
                                                              2.82
                       (d, J=8.6Hz; Z form), 7.76(d, J=
                                        1367, 1242,   74.97
                                                          7.13
                                                              2.91
                       2.2Hz; Z form), 7.87(d, J=2.0Hz;
                                        1004
                       E form)
    42    white 236-238
                       (DMSO-d.sub.6)2.4-3.7(m, 10H), 4.95-
                                        (KBr tablet)
                                                444(M+)
                                                      C.sub.27 H.sub.25
                                                      FN.sub.2 O.sub.3.C.sub.3
                                                       H.sub.8 O.
    (E-73b')
          crystal
                (dec.) 5.65(m, 2H), 6.17(t, J=6.7Hz,
                                        1608, 1509,   H.sub.2 O
                [isopro-
                       1H), 6.83(d, J=8.5Hz, 1H), 6.85-
                                        1370, 1224    C   H   N
                panol] 7.55(m, 8H), 7.72(dd, J=2.2,   69.10
                                                          6.60
                                                              5.33
                       8.5Hz, 1H), 7.92(d, J=2.2Hz, 1H)
                                                      68.95
                                                          6.75
                                                              5.36
    43    pale  161-165
                       (DMSO-d.sub.6)2.3-3.8(m, 10H), 4.9-
                                        (KBr tablet)
                                                428(M+)
                                                      C.sub.25 H.sub.24
                                                      N.sub.4 O.sub.3
    (E/Z-76b)
          yellow
                [isopro-
                       5.65(m, 2H), 5.86(t, J=7.1Hz; Z
                                        1584, 1551,   C   H   N
          crystal
                panol] form), 6.18(t, J=6.6Hz; E form),
                                        1487, 1450,   69.91
                                                          5.78
                                                              13.22
                       6.6-8.4(m, 10H)  1360          70.08
                                                          5.65
                                                              13.08
    44    white   203-204.5
                       (DMSO-d.sub.6)1.1-2.55(m, 9H), 2.46
                                        (KBr tablet)
                                                453(M+)
                                                      C.sub.30 H.sub.31
                                                      NO.sub.3.0.5C.sub.4
                                                      H.sub.4 O.sub.4
    (E-96b')
          solid [acetone]*
                       (d, J=6.6Hz, 2H), 2.92(d, J=6.6
                                        1704, 1488,   C   H   N
                       Hz, 1H), 3.48(s, 2H), 4.0-5.5(m,
                                        1357, 1249,   74.92
                                                          6.64
                                                              2.79
                       2H), 6.08(t, J=6.6Hz, 1H), 6.57
                                        1227, 1003    75.12
                                                          6.50
                                                              2.74
                       (s, 1H), 6.67(d, J=8.4Hz, 1H),
                       7.0-7.5(m, 11H)
    45    white 260-262
                       (DMSO-d.sub.6)1.5-3.6(m, 10H), 3.51
                                        (KBr tablet)
                                                495(M+)
                                                      C.sub.30 H.sub.29
                                                      N.sub.3 O.sub.4.H.sub.2
                                                      O
    (E-98b')
          solid [isopro-
                       (s, 2H), 4.05-4.2(m, 1H), 4.93&
                                        1699, 1489,   C   H   N
                panol]*
                       5.40(each bs, 2H), 6.13(t, J=6.7
                                        1386, 1003    70.31
                                                          6.45
                                                              8.35
                       Hz, 1H), 6.68(d, J=8.5Hz, 1H), 70.16
                                                          6.08
                                                              8.18
                       6.95-7.5(m, 10H)
    46    white   218-219.5
                       (DMSO-d.sub.6)1.5-2.5(m, 4H), 2.9-
                                        (KBr tablet)
                                                --    C.sub.30 H.sub.28
                                                      N.sub.3 O.sub.4 Na
     (E-98b")
          crystal
                [isopro-
                       3.4(m, 6H), 3.15(s, 2H), 4.0-4.15
                                        1681, 1567,   C   H   N
                panol] (m, 1H), 4.2-5.6(m, 2H), 6.10(t,
                                        1485, 1381,   69.66
                                                          5.52
                                                              8.22
                       J=6.7Hz, 1H), 6.57(d, J=8.3Hz,
                                        1009          69.62
                                                          5.45
                                                              8.12
                       1H), 6.9-7.5(m, 10H), 8.29(s, 1H)
    __________________________________________________________________________

EXAMPLE 47

Methyl 11-[2-(4-cinnamyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2 -carboxylate (Compound 20a):

Compound k, 2.0 g, obtained in Reference Example 11 and 1.2 g of cinnamyl bromide were stirred in 100 ml of isopropanol for 4 hours at room temperature. The mixture was extracted with 300 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=10:10:1) to give 0.8 g of the objective compound as pale yellow oil.

EXAMPLE 48

Methyl (E)-11-[3-(4-cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxe pin-2-carboxylate (Compound E-75a):

The objective compound was prepared using Compound s obtained in Reference Example 19 and cinnamyl bromide in a manner similar to Example 47.

In Examples 49 and 50 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives and then converting the hydrolyzate into the fumarate in a manner similar to Example 44.

EXAMPLE 49

11-[2-(4-Cinnamyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2- carboxylic acid.difumarate.0.5 hydrate (Compound 20b')

EXAMPLE 50

(E)-11-[3-(4-Cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2-carboxylic acid.difumarate.0.5 hydrate (Compound E-75b')

Physicochemical properties of the compounds obtained in Examples 47 to 50 are shown in Table 7-3.

                                      TABLE 7-3
    __________________________________________________________________________
               MP (.degree.C.)
    Example    [Solvent
    No.        for re-                            Elemental analysis (%)
    (Compound
          Appear-
               crystal-
                    NMR              IR      MS   Upper column: found
    No.)  ance lization]
                    (solvent) .delta., ppm
                                     (method) cm.sup.-1
                                             m/z  Lower column:
    __________________________________________________________________________
                                                  calcd
    47    pale --   (CDCl.sub.3)2.32-2.80(m, 12H), 3.14
                                     (neat)  514(M+)
                                                   --
    (20a) yellow    (d, J=5.6Hz, 2H), 3.89(s, 3H),
                                     2944, 2808,
          oil       4.89&6.45(ABq, J=14.5Hz, 2H),
                                     1708, 1610,
                    5.10(s, 1H), 6.21-8.10(m, 14H)
                                     1571, 1497,
                                     1007
    48    colorless
               --   (CDCl.sub.3)2.48(m, 9H), 3.0-3.3(m,
                                     (neat)  480(M+)
                                                   --
    (E-75a)
          oil       4H), 3.81(s, 3H), 4.9-5.7(m, 2H),
                                     1715, 1606,
                    6.05-6.5(m, 2H), 6.71(d, J=9.2Hz,
                                     1245, 1006
                    1H), 7.0-7.5(m, J=9.2Hz, 9H),
                    7.73(dd, J=2.2, 9.2Hz, 1H), 7.99
                    (d, J=2.2Hz, 1H)
    49    yellow
               210-211
                    (DMSO-d.sub.6)2.35-2.7(m, 12H), 3.25
                                     (KBR tablet)
                                             500(M+)
                                                  C.sub.38 H.sub.40 N.sub.2
                                                  O.sub.11 S.0.5H.sub.2 O
     (20b')
          solid
               [aceto-
                    (d, J=6.6Hz, 2H), 5.05&6.25(ABq,
                                     1713, 1612,  C   H   N
               nitrile]*
                    J=10.6Hz, 2H), 5.44(s, 1H), 6.25-
                                     1300, 1252,  61.48
                                                      5.42
                                                          3.88
                    6.3(m, 1H), 6.87(d, J=8.5Hz, 1H),
                                     1170         61.53
                                                      5.57
                                                          3.78
                    7.2-7.5(m, 10H), 7.71(dd, J=2.2,
                    8.5Hz, 1H), 7.98(d, J=2.2Hz, 1H)
    50    white
               246  (DMSO-d.sub.6)2.4-3.3(m, 10H), 3.24
                                     (KBr tablet)
                                             466(M+)
                                                  C.sub.38 H.sub.38 N.sub.2
                                                  O.sub.11.0.5H.sub.2 O
     (E-75b')
          crystal
               (dec.)
                    (d, J=6.7Hz, 2H), 4.9-5.7(m, 2H),
                                     1703, 1659,  C   H   N
               [aceto-
                    6.14(t, J=6.7Hz, 1H), 6.2-6.35
                                     1605, 1250,  64.53
                                                      5.43
                                                          4.05
               nitrile]
                    (m, 1H), 6.82(d, J=8.5Hz, 1H),
                                     1010, 980    64.49
                                                      5.55
                                                          3.96
                    7.2-7.55(m, 10H), 7.72(dd, J=
                    2.2, 8.5Hz, 1H), 7.90(d, J=2.2Hz,
                    1H)
    __________________________________________________________________________

EXAMPLE 51

Methyl 11-[2-[4-(4-fluorophenylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodib enz[b,e]oxepin-2-carboxylate (Compound 22a):

Compound k, 0.8 g, obtained in Reference Example 11 was dissolved in 50 ml of pyridine and 0.5 g of 4fluorobenzenesulfonyl chloride was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate: triethylamine=50:20:1) to give 0.6 g of the crude product. The crude product obtained was recrystallized from isopropyl ether to give 0.4 g of the objective compound.

In Examples 52 and 53 below, the objective compound was prepared using Compound k and the corresponding sulfonyl- chloride compound in a manner similar to Example 51.

EXAMPLE 52

Methyl 11-[2-[4-(styrylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 24a)

EXAMPLE 53

Methyl 11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b ,e]oxepin-2-carboxylate (Compound 25a)

In Examples 54 and 55 below, the objective compound was prepared using Compound k and the corresponding acid chloride compound in a manner similar to Example 51.

EXAMPLE 54

Methyl 11-[2-[4-(2,3,4-trimethoxybenzoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodi benz[b,e]oxepin-2-carboxylate (Compound 27a)

EXAMPLE 55

Methyl 11-[2-[4-(cinnamoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepi n-2-carboxylate (Compound 28a)

EXAMPLE 56

Methyl 11-[2-[4-(phenoxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e ]oxepin-2-carboxylate (Compound 30a):

Compound k, 2.0 g, obtained in Reference Example 11 was dissolved in 100 ml of isopropanol and 0.75 ml of phenyl chloroformate was added to the solution followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure and the resulting residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate: triethylamine=50:30:1) to give 1.7 g of the crude product. The crude product obtained was solidified with isopropyl ether to give 1.6 g of the objective compound.

EXAMPLE 57

Methyl 11-[2-[4-(benzyloxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b ,e]oxepin-2-carboxylate (Compound 31a)

The objective compound was prepared using Compound k and benzyl chloroformate in a manner similar to Example 56.

In Examples 58 and 59 below, the objective compound was prepared from Compound s obtained in Reference Example 19 and the corresponding sulfonyl chloride compound in a manner similar to Example 51.

EXAMPLE 58

Methyl (E)-11-[2-[4-(styrylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid (Compound E-78a)

EXAMPLE 59

Methyl (E)-11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodib enz[b,e]oxepin-2-carboxylic acid (Compound E-79a)

EXAMPLE 60

Methyl 11-[2-[4-(1-naphthalenesulfonyl)-1-homopiperazinyl]ethyl]thio-6,11-dihydro dibenz[b,e]oxepin-2-carboxylate (Compound 34a):

The objective compound was prepared using 1.4 g of Compound u obtained in Reference Example 21 and 1.0 g of 1-naphthalenesulfonyl chloride in a manner similar to Example 51.

Physicochemical properties of the compounds obtained in Examples 51-to 60 are shown in Table 7-4.

                                      TABLE 7-4
    __________________________________________________________________________
                MP (.degree.C.)
    Example     [Solvent
    No.         for re-                           Elemental analysis (%)
    (Compound
          Appear-
                crystal-
                     NMR             IR      MS   Upper column: found
    No.)  ance  lization]
                     (solvent) .delta., ppm
                                     (method) cm.sup.-1
                                             m/z  Lower column:
    __________________________________________________________________________
                                                  calcd.
    51    yellow
                80-82
                     (CDCl.sub.3)2.25-3.15(m, 12H), 3.80
                                     (KBr tablet)
                                             556(M+)
                                                  C.sub.28 H.sub.29 FN.sub.2
                                                  O.sub.5 S.sub.2
    (22a) amorphous
                [iso-
                     (s, 3H), 4.85&6.39(ABq, J=13.6
                                     1702, 1494,  C   H   N
                propyl
                     Hz, 2H), 5.00(s, 1H), 6.77(d, J=
                                     1357, 1326,  60.60
                                                      5.39
                                                          4.88
                ether]*
                     8.6Hz, 1H), 6.95-8.0(m, 10H)
                                     1244, 1172,  60.41
                                                      5.25
                                                          5.03
                                     1004
    52    colorless
                --   (CDCl.sub.3)2.4-2.75(m, 8H), 3.15-
                                     (KBr tablet)
                                             550(M+)
                                                   --
    (24a) oil        3.35(m, 4H), 3.79(s, 3H), 4.97
                                     1715, 1607,
                     (s, 1H), 4.82&6.37(ABq, J=19.2
                                     1310, 1248,
                     Hz, 2H), 6.7-6.85(m, 2H), 7.1- 7.5
                                     1152, 1000
                     (m, 10H), 7.71(dd, J=3.0, 12.9Hz,
                     1H), 7.90(d, J=3.0Hz, 1H)
    53    yellow
                80-81
                     (CDCl.sub.3)2.28-3.26(m, 12H), 3.81
                                     (KBr tablet)
                                             544(M+)
                                                  C.sub.26 H.sub.28 NO.sub.5
                                                  S.sub.3
    (25a) solid [iso-
                     (s, 3H), 5.00(s, 1H), 4.86&6.36
                                     1714, 1609,  C   H   N
                propyl
                     (ABq, J=13.2Hz, 2H), 6.68-7.98
                                     1353, 1242,  57.31
                                                      5.30
                                                          5.09
                ether]*
                     (m, 10H)        1007         57.33
                                                      5.18
                                                          5.14
    54    colorless
                --   (CDCl.sub.3)2.15-2.75(m, 10H), 3.15-
                                     (CHCl.sub.3)
                                             592(M+)
                                                   --
    (27a) oil        3.45(m, 2H), 3.8-3.9(m, 12H),
                                     1713, 1613,
                     5.04(s, 1H), 4.87&6.38(ABq, J=
                                     1461, 1295,
                     17.1Hz, 2H), 6.62(d, J=12.9Hz,
                                     1120, 1009
                     1H), 6.80(d, J=12.9H, 1H), 6.91
                     (d, J=12.9Hz, 1H), 7.1-7.47(m,
                     4H), 7.74(dd, J=3.0, 12.9Hz, 1H),
                     7.93(d, J=3.0Hz, 1H)
    55    yellow
                --   (CDCl.sub.3)2.19-2.70(m, 8H), 3.36-
                                     (KBr tablet)
                                             528(M+)
                                                   --
    (28a) amorphous  3.83(m, 4H), 3.83(s, 3H), 5.03(s,
                                     1711, 1645,
                     1H), 4.85&6.41(ABq, J=12.8Hz,
                                     1606, 1245,
                     2H), 6.61-8.06(m, 14H)
                                     982
    56    white 133-135
                     (CDCl.sub.3)2.2-2.8(m, 8H), 3.3-3.7
                                     (KBr tablet)
                                             518(M+)
                                                  C.sub.29 H.sub.30 N.sub.2
                                                  O.sub.5 S
    (30a) solid [iso-
                     (m, 4H), 3.85(s, 3H), 4.87&6.43
                                     1712, 1611,  C   H   N
                propyl
                     (ABq, J=12.8Hz, 2H), 5.04(s,
                                     1497, 1293,  67.00
                                                      5.90
                                                          5.12
                ether]
                     1H), 6.83(d, J=8.4Hz, 1H), 6.95-
                                     1248, 1199,  67.16
                                                      5.83
                                                          5.40
                     7.5(m, 9H), 7.76(dd, J=2.4,
                                     1118
                     8.4Hz, 1H), 7.97(d, J=2.4Hz, 1H)
    57    colorless
                --   (CDCl.sub.3)2.05-2.8(m, 8H), 3.4-
                                     (neat)  532(M+)
                                                   --
    (31a) oil        3.65(m, 4H), 3.80(s, 3H), 4.84&
                                     2948, 1710,
                     6.39(ABq, J=12.6Hz, 2H), 5.02(s,
                                     1610, 1433,
                     1H), 5.08(s, 2H), 6.81(d, J=8.5
                                     1237, 1118,
                     Hz, 1H), 7.0-7.5(m, 9H), 7.74
                                     1006
                     (dd, J=2.4, 8.5Hz, 1H), 7.93(d,
                     J=2.4Hz, 1H)
    58    pale  193-196
                     (CDCl.sub.3)2.45-2.9(m, 4H), 3.0-3.6
                                     (KBr tablet)
                                             530(M+)
                                                  C.sub.30 H.sub.30 N.sub.2
                                                  O.sub.5 S
    (E-78a)
          yellow
                [isopro-
                     (m, 6H), 3.91(s, 3H), 4.7-5.7(m,
                                     1715, 1607,  C   H   N
          crystal
                panol]
                     2H), 6.23(t, J=7.6Hz, 1H), 6.5-
                                     1310, 1248,  67.55
                                                      5.90
                                                          5.39
                     8.1(m, 14H)     1152, 1000,  67.90
                                                      5.70
                                                          5.28
                                     945
    59    colorless
                --   (CDCl.sub.3)2.45-2.6(m, 4H), 3.0-
                                     (KBr tablet)
                                             510(M+)
                                                   --
    (E-79a)
          oil        3.3(m, 6H), 3.86(s, 3H), 4.7-5.7
                                     1711, 1605,
                     (m, 2H), 6.13(t, J=6.8Hz, 1H),
                                     1351, 1241,
                     7.0-7.65(m, 7H), 7.78(dd, J=2.2,
                                     999
                     8.6Hz, 1H), 6.77(d, J=8.6Hz,
                     1H), 7.98(d, J=2.2Hz, 1H)
    60    colorless
                --   (CDCl.sub.3)1.6-2.0(m, 2H), 2.45-
                                     (KBr tablet)
                                             602(M+)
                                                   --
    (34a) oil        2.85(m, 8H), 3.3-3.6(m, 4H), 3.86
                                     1713, 1609,
                     (s, 3H), 4.88&6.43(ABq, J=12.1
                                     1321, 1243,
                     Hz, 2H), 4.99(s, 1H), 7.25-8.85
                                     1005
                     (m, 13H)
    __________________________________________________________________________

In Examples 61 through 63 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.

EXAMPLE 61

11-[2-[4-(Styrylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid.0.5 hydrate (Compound 24b')

EXAMPLE 62

11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b, e]oxepin-2-carboxylic acid.0.5 isopropanol.dihydrate (Compound 25b')

EXAMPLE 63

11-[2-[4-(2,3,4-Trimethoxybenzoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodib enz[b,e]oxepin-2-carboxylic acid (Compound 27b)

EXAMPLE 64

11-[2-[4-(2,3,4-Trimethoxybenzoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodib enz[b,e]oxepin-2-carboxylic acid. monohydrochloride.1.1 hydrate (Compound 27b')

The objective compound was prepared as the hyd.rochloride from Compound 27b obtained in Example 63 in a manner similar to Example 2.

In Examples 65 through 68 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.

EXAMPLE 65

11-[2-[4-(Cinnamoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin -2-carboxylic acid (Compound 28b)

EXAMPLE 66

11-[2-[4-(Benzyloxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b, e]oxepin-2-carboxylic acid.dihydrate (Compound 31b')

EXAMPLE 67

(E)-11-[2-[4-(Styrylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylic acid.0.1 isopropanol.0.1 hydrate (Compound E-78b')

EXAMPLE 68

(E)-11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibe nz[b,e]oxepin-2-carboxylic acid.0.5 hydrate (Compound E-79b')

Physicochemical properties of the compounds obtained in Examples 61 to 68 are shown in Table 7-5.

                                      TABLE 7-5
    __________________________________________________________________________
                MP (.degree.C.)
    Example     [Solvent
    No.         for re-                           Elemental analysis (%)
    (Compound
          Appear-
                crystal-
                     NMR             IR      MS   Upper column: found
    No.)  ance  lization]
                     (solvent) .delta., ppm
                                     (method) cm.sup.-1
                                             m/z  Lower column:
    __________________________________________________________________________
                                                  calcd.
    61    white 232-235
                     (DMSO-d.sub.6)2.3-2.7(m, 8H), 3.0-
                                     (KBr tablet)
                                             --   C.sub.29 H.sub.30 N.sub.2
                                                  O.sub.5 S.sub.2.0.5H.sub.2
                                                  O
    (24b')
          crystal
                [isopro-
                     3.3(m, 4H), 5.44(s, 1H), 5.10&
                                     1685, 1603,  C   H   N
                panol]
                     6.31(ABq, J=19.2Hz, 2H), 6.86
                                     1313, 1246,  62.30
                                                      5.63
                                                          4.82
                     (d, J=13.5Hz, 1H), 7.25-7.65(m,
                                     1157, 1002,  62.23
                                                      5.58
                                                          5.00
                     10H), 7.65-7.9(m, 2H), 7.98(d, J=
                                     957
                     3.0Hz, 1H)
    62    white 167-168
                     (DMSO-d.sub.6)2.50-3.46(m, 12H),
                                     (KBr tablet)
                                             530(M+)
                                                  C.sub.25 H.sub.26 N.sub.2
                                                  O.sub.5 S.sub.3.0.5
     (25b')
          crystal
                [isopro-
                     5.05&6.17(ABq, J= 12.7Hz, 2H),
                                     3400, 2860,  C.sub.3 H.sub.8 O.2H.sub.2
                                                  O
                panol]
                     5.47(s, 1H), 6.86-8.11(m, 10H),
                                     1687, 1607,  C   H   N
                     12.76(bs, 1H)   1354, 1159   53.53
                                                      5.20
                                                          4.55
                                                  53.34
                                                      5.41
                                                          4.69
    63    pale  --   (DMSO-d.sub.6)2.85-3.65(m, 12H),
                                      --     578(M+)
                                                   --
    (27b) yellow     3.75-3.85(m, 9H), 5.52(s, 1H),
          amorphous  5.09&6.15(ABq, J=12.9Hz, 2H),
                     6.85-7.00(m, 3H), 7.4-7.5(m, 4H),
                     7.73(dd, J=2.1, 8.6Hz, 1H),
                     8.04(d, J=2.1Hz, 1H)
    64    white 165-168
                      --             (KBr tablet)
                                             --   C.sub.31 H.sub.34 N.sub.2
                                                  O.sub.7 S.HCl.1H.sub.2 O
    (27b')
          crystal
                [iso-                2934, 1583,  C   H   N
                propyl               1462, 1227,  58.63
                                                      6.23
                                                          4.23
                ether]               1011         58.64
                                                      5.90
                                                          4.41
    65    white 218-219
                     (DMSO-d.sub.6)2.25-3.75(m, 12H),
                                     (KBr tablet)
                                             514(M+)
                                                  C.sub.30 H.sub.30 N.sub.2
                                                  O.sub.4 S
     (28b)
          crystal
                [isopro-
                     5.05&6.28(ABq, J=12.5Hz, 2H),
                                     1692, 1642,  C   H   N
                panol]
                     5.45(s, 1H), 6.87(d, J=8.5Hz,
                                     1566, 1227,  69.91
                                                      5.96
                                                          5.39
                     1H), 7.24(d, J=15.5Hz, 1H), 7.3-
                                     1004, 987    70.02
                                                      5.88
                                                          5.44
                     7.5(m, 5H), 7.48(d, J=15.5Hz,
                     1H), 7.65-7.8(m, 3H), 8.00(d, J=
                     2.1Hz, 1H)
    66    white 207-208
                     (DMSO-d.sub.6)2.8-4.2(m, 12H), 5.12
                                     (KBr tablet)
                                             518(M+)
                                                  C.sub.29 H.sub.30 N.sub.2
                                                  O.sub.5 S.2H.sub.2 O
    (31b')
          crystal
                [toluene]
                     (s, 2H), 5.09&6.15(ABq, J=12.9
                                     1714, 1677,  C   H   N
                     Hz, 2H), 5.52(s, 1H), 6.90(d, J=
                                     1611, 1436,  62.43
                                                      6.51
                                                          4.96
                     8.6Hz, 1H), 7.3-7.6(m, 9H), 7.73
                                     1200, 1161,  62.80
                                                      6.18
                                                          5.05
                     (dd, J=2.2, 8.6Hz, 1H), 8.04(d,
                                     1005
                     J=2.2Hz, 1H), 11.25(bs, 1H)
    67    white 233-235
                     (DMSO-d.sub.6)2.2-3.5(m, 10H),
                                     (KBr tablet)
                                             516(M+)
                                                  C.sub.29 H.sub.28 N.sub.2
                                                  O.sub.5 S.
    (E-78b')
          crystal
                (dec.)
                     5.00&5.52(each bs, 2H), 6.10(t, J=
                                     1685, 1603,  0.5H.sub.2 O.0.1C.sub.3
                                                  H.sub.8 O
                [isopro-
                     6.6Hz, 1H), 6.83(d, J=8.5Hz,
                                     1570, 1348,  C   H   N
                panol]
                     1H), 7.2-7.9(m, 11H)
                                     1313, 1246,  66.37
                                                      5.70
                                                          5.11
                                     1002, 957    66.20
                                                      5.65
                                                          5.27
    68   white  250-251
                     (DMSO-d.sub.6)2.3-3.5(m, 10H),
                                     (KBr tablet)
                                             496(M+)
                                                  C.sub.25 H.sub.24 N.sub.2
                                                  O.sub.5 S.sub.2.0.5H.sub.2
                                                  O
    (E-79b')
         crystal
                (dec.)
                     4.99&5.50(each bs, 2H), 6.07(bs,
                                     1685, 1607,  C   H   N
                [isopro-
                     1H), 6.82(d, J=8.5Hz, 1H), 7.2-
                                     1353, 1316,  59.33
                                                      4.74
                                                          5.47
                panol]
                     7.65(m, 6H), 7.71(dd, J=2.2, 8.5
                                     1246, 1166,  59.39
                                                      4.98
                                                          5.54
                     Hz, 1H), 7.87(d, J=2.2Hz, 1H),
                                     1009, 954
                     8.05-8.10(m, 1H)
    __________________________________________________________________________

Pharmaceutical Preparation 1

Tablet

A tablet having the following composition is prepared in a conventional manner.

    ______________________________________
    Compound 1b'     100 mg
    Lactose          60 mg
    Potato starch    30 mg
    Polyvinyl alcohol
                      2 mg
    Magnesium stearate
                      1 mg
    Tar pigment      trace
    ______________________________________

Pharmaceutical Preparation 2

Powder

Powders having the following composition are prepared in a conventional manner.

    ______________________________________
    Compound 38b'   100 mg
    Lactose         300 mg
    ______________________________________

Pharmaceutical Preparation 3

Syrup

Syrup having the following composition is prepared in a conventional manner.

    ______________________________________
    Compound 38b'           100    mg
    Refined sugar           30     g
    Ethyl p-hydroxybenzoate 40     mg
    Propyl p-hydroxybenzoate
                            10     mg
    Starwberry flavor       0.1    cc
    Water is added until the whole volume is 100 cc.
    ______________________________________

Pharmaceutical Preparation 4

Tablet

A tablet having the following composition is prepared in a conventional manner.

    ______________________________________
    Compound E-78b'  100 mg
    Lactose          60 mg
    Potato starch    30 mg
    Polyvinyl alcohol
                      2 mg
    Magnesium stearate
                      1 mg
    Tar pigment      trace
    ______________________________________

Pharmaceutical Preparation 5

Syrup

Syrup having the following composition is prepared in a conventional manner.

    ______________________________________
    Compound E-78b'         100    mg
    Refined sugar           30     g
    Ethyl p-hydroxybenzoate 40     mg
    Propyl p-hydroxybenzoate
                            10     mg
    Strawberry flavor       0.1    cc
    Water is added until the whole volume is 100 cc.
    ______________________________________

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

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Current U.S. Class:	514/320; 514/212.01; 514/217.11; 514/382; 514/422; 540/596; 544/359; 544/366; 544/370; 544/375; 544/380; 546/16; 546/196; 546/202; 546/203; 546/204; 548/251; 548/525; 548/527
Intern'l Class:	A61K 031/445; C07D 405/12
Field of Search:	546/196 540/596 548/251,525 514/213,320,422,382